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1
Guyonnet, Léa. "Rôle du récepteur myéloïde à l’endothéline (ETB) au cours de l’hypertension artérielle." Thesis, Sorbonne Paris Cité, 2016. http://www.theses.fr/2016USPCB018.
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L’hypertension artérielle (HTA) est un problème de santé publique. Largement répandue dans le monde, elle touchait 40% des adultes âgés de plus de 25 ans et causait 9.4 millions de décès en 2008. Cette pathologie est la cause la plus commune de décès dans les pays développés et constitue un facteur de risque majeur d’atteintes cardiaques, rénales et cérébrales. Bien qu'étudiés depuis maintenant plus d'un demi-siècle, les mécanismes des atteintes systémiques liées à l'hypertension restent encore peu connus. L'augmentation de la pression artérielle est multifactorielle et découle aussi du dérèglement de certains systèmes tels le système rénine-angiotensine et le système endothéline. De récentes études ont suggéré un rôle de l’immunité innée dans le développement de l’HTA et des lésions qui y sont associées. L’endothéline-1 est un puissant vasoconstricteur. Sa production est déclenchée par différents stimuli dont l’AngII et des cytokines pro-inflammatoires. L’ET-1 agit via deux récepteurs : ETAR et ETBR. Pour ce projet, nous avons généré des souris ne possédant pas le récepteur ETB myéloïde (LysM-Cre Ednrb lox/lox). Ces souris ont été soumises à une perfusion chronique d’AngII associée à un régime hyper-sodé. Nous avons observé que les deux groupes de souris développent la même hypertension et les mêmes atteintes cardiaques. En revanche les atteintes des organes cibles sont moins importantes chez les souris LysM-Cre Ednrb lox/lox. La fonction rénale de ces dernières est préservée et, histologiquement, moins de lésions sont observées. Cette protection semble être due à l’incapacité des cellules myéloïdes à infiltrer les reins. En effet, la chimioattraction des cellules myéloïdes vers ET-1 est dépendante du récepteur ETB myéloïde. De plus, les cellules inflammatoires qui sont observées dans les reins des souris LysM-Cre Ednrb lox/lox présentent un phénotype anti-inflammatoire contrairement à leur contrôlesArterial hypertension is a major risk factor for atherosclerosis, coronary artery disease, stroke, and chronic kidney disease (CKD) and is one of the most prominent contributors to death worldwide. However, despite the frequency of hypertension, its cause in the majority of adults is unknown. Hypertension is complex, with no single mechanism entirely explaining the blood pressure (BP) rise in any given model. The past 50 years have seen growing evidence implicating the immune system. Recent data suggest that macrophages (M)/monocytes contribute to, and protect from, hypertension and its associated end organ injury. Endothelin-1 (ET-1) is the most potent endogenous vasoconstrictor. Its production is triggered by multiple stimuli including Ang II and pro-inflammatory cytokines. ET-1 acts by binding to two distinct receptors, the endothelin-A (ETA) and the endothelin-B (ETB) receptors. Interestingly, ET antagonism can blunt BP elevation in an Ang II model suggesting that ET-1 largely mediates the effects of Ang II. Here, we have generated mice specifically lacking ETB receptors on myeloid cells. We have shown that the development of hypertension associated with Ang II infusion is not dependent on these cells. Similarly, the cardiac dysfunction seen after 6 weeks of Ang II was similar between knockout and control mice. Interestingly, mice deficient of ETB receptors on myeloid cells alone were protected from Ang II induced vascular dysfunction and kidney injury. This protection appeared to relate to an inability for ETB receptor deficient Mto infiltrate the kidneys due to impaired chemokinesis towards ET-1. Furthermore, the Minfiltrating he kidney in response to Ang II in myeloid ETB receptor deficient mice overwhelmingly possessed an anti-inflammatory phenotype
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Sedkaoui, Melissa. "Single-chain variable fragments and molecularly imprinted polymers directed against endothelin receptors – type B for cancer cells targeting." Thesis, Compiègne, 2021. http://www.theses.fr/2021COMP2636.
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Les récepteurs aux endothélines sont des récepteurs couples aux protéines G desquels deux variants existent, type A (ETAR) et type B (ETBR). Ils sont principalement décrits pour leur rôle physiologique de régulation du flux sanguin dans tous les types de vaisseaux via les mécanismes de vasoconstriction et de dilatation, respectivement. Cependant, les récepteurs aux endothélines sont impliqués dans plusieurs désordres physiologiques dont le cancer ou l’expression de l’un ou des deux récepteurs aux endothélines est dérégulée. Nous avons développé deux stratégies complémentaires pour le ciblage des récepteurs ETB, visant à inhiber son action quand il est surexprimé : la sélection de single-chain variable fragment (scFv) à partir d’une banque large et naïve par la technologie du phage-display, et la synthèse sur mesure, assistée par une matrice de polymères à empreintes moléculaires (MIP) comme « anticorps en plastique ». La sélection de scFv a été réalisée par biopanning sur cellules transfectées entières afin de maintenir la conformation native de ETBR. Phage-scFv qui se lient uniquement à la cible et ceux qui sont internalisés suite à l’interaction scFv- récepteur ont été isolés séparément. Après confirmation de la reconnaissance des cellules CHO-ETBR par rapport aux cellules CHO-WT par les phages-scFv polyclonaux en utilisant un test ELISA et la microscopie électronique à balayage (MEB), nous avons sélectionné au total 17 clones qui ont montré une capacité de liaison augmentée par phage-ELISA monoclonal sur cellules transfectées entières, mais également sur UACC-257, une lignée cellulaire de mélanome avec une surexpression de ETBR. Des résultats préliminaires obtenus par cryométrie en flux ont montré une reconnaissance augmentée de CHO-ETBR par l’un des clones sélectionnés. La viabilité cellulaire a été affectée par certains de ces clones. Des MIP nanoparticules ont été synthétisées en utilisant un peptide synthétique comme molécule matrice qui mime un « épitope » de ETBR. Nous avons réalisé la synthèse sur une phase solide afin d’obtenir une exposition orientée de la matrice, résultant en la production de MIP avec des cavités homogènes. Les particules MIP d’une taille de l’ordre du nanomètre ont été obtenus et ont par la suite été testés pour leur capacité à reconnaitre le récepteur entier exprimé sur la surface cellulaire par imagerie cellulaire. Des nano-MIP fluorescents ont montré une reconnaissance sélective des cellules transfectées par rapport à leurs homologues non transfectéesEndothelin receptors are G-protein coupled receptors of which two variants exist, type A (ETAR) and type B (ETBR). They are mainly described for their physiological role of regulating the blood flow in all vessel types via vasoconstriction and vasodilatation mechanisms, respectively. However, endothelin receptors are involved in several physiological disorders including cancer in which the expression of one or both endothelin receptors are deregulated.We have developed two complementary strategies for targeting ETB receptors, aiming to inhibit its action when it is overexpressed: selection of single-chain variable fragments (scFv) from a large naive library by phage-display technology as « biologic antibodies », and tailor-made template-assisted synthesis of Molecularly Imprinted Polymers (MIP) as « plastic antibodies ». The selection of scFv was performed by biopanning on whole transfected cells in order to maintain the native conformation of ETBR. Phage-scFv that only bind to the target and the ones that are internalized subsequently to scFv-receptor interaction were isolatedseparately. After confirming the recognition of CHO-ETBR cells over CHO-WT cells by polyclonal phage-scFv using an ELISA assay and Scanning Electron Microscopy (S.E.M), we have selected in total 17 clones that showed increased binding ability by monoclonal phage-ELISA on whole transfected cells but also to UACC-257, a melanoma cell line with an overexpression of ETBR. Preliminary results obtained by flow cytometry showed an enhanced recognition of CHO-ETBR by one of the selected clones. Cell viability was shown to be affected by some of these clones. MIP nanoparticles were synthesized using a synthetic peptide as template molecule that mimics an « epitope » of ETBR. We performed the synthesis on a solid phase in order to obtain an oriented exposition of the template resulting in the production of MIPs with homogenous cavities. MIP particles of a size in the nanometer range were obtained and were subsequently tested for their ability to recognize the whole receptor expressed oncell surface by cell imaging. Fluorescent nano-MIPs were shown to recognize selectively transfected cells with regard to their non-transfected counterparts
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Swire, Matthew. "Investigating endothelin receptor B signalling during myelination." Thesis, University of Edinburgh, 2017. http://hdl.handle.net/1842/28912.
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A key process enabling the correct functioning of neural circuits involves the formation of multi‐layered membranous myelin sheaths around axons. Myelin sheaths, made by specialised glial cells called oligodendrocytes in the central nervous system (CNS), metabolically support underlying axons and speed up electrical impulse conduction, aiding efficient communication between neurons. As only a subset of axons in the CNS are myelinated, with unique patterns developed therein, it raises the questions: how does an oligodendrocyte choose which axon to myelinate and what regulates the amount of myelin made? The production of myelin sheaths by the oligodendrocyte, is under strong influence from of a range of signals including those mediated by G protein‐coupled receptor (GPR) superfamily members. One GPR, Endothelin receptor B (EDNRB), best known for regulating blood flow, had previously been demonstrated to both positively and negatively influence myelination. I have investigated how EDNRB regulates myelination using an in vitro myelination assay, alongside in vivo analysis in zebrafish and mice. These systems identified a direct signalling role for EDNRB in the promotion of myelin sheath number. Furthermore, profiling the protein signalling cascade downstream of this receptor identified a range of known and novel factors involved in the regulation of myelin sheath number including the MAPK pathway, Src family kinases, ErbB receptors, protein kinase C ε, NMDAR and AMPAR. Functional analyses of a subset of these factors elucidate how EDNRB signalling, potentially connecting signals from a range of cell types, ensures correct adequate myelination in the CNS.
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Bagnall, Alan. "Role of the endothelin B receptor in cardiovascular homeostasis." Thesis, University of Edinburgh, 2004. http://hdl.handle.net/1842/24786.
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The aim of this project was to precisely determine the role of the endothelial cell (EC) ETB receptor in the regulation of vascular tone, blood pressure and clearance of ET-1. Cre-loxP recombination was utilised to conditionally regulate ETB receptor expression in vivo. Mice featuring loxP sites flanking exons 2 and 3 of the ETB receptor gene (floxed ETB receptor mice) were generated by standard gene targeting techniques in embryonic stem cells. Floxed ETB mice were crossed with Tie2-Cre transgenic mice to produce mice in which recombination-mediated removal of ETB receptor coding regions was limited to EC (Flox/Flox Tie2). EC ETB receptor binding of 125I ET-1 and in vitro aortic and tracheal ring myography were performed to assess endothelial function and the response to selective ETB receptor agonists. Pulmonary EC ET-1 binding was decreased by ~80% in EC-specific ETB receptor knockout mice (cpm/50μg membrane protein ± SEM; Flox/Flox Tie2 581 ± 67; W/W -/- 3175 ± 268; n=3; p<0.001). Cell-specificity of ETB receptor down-regulation was demonstrated by maintenance of normal ETB receptor-mediated tracheal constriction. Blood pressure was increased in Flox/Flox Tie2 mice (MAP 137.2 ± 6.4mmHg (n=5); W/W -/-, 113.7 ± 4.7mmHg (n=6; p<0.05) but was not affected by dietary salt. Plasma ET-1 was increased ~4 fold following EC ETB receptor down-regulation (mean plasma [ET-1] pg/ml ± SEM; Flox/Flox Tie2 12.40 ± 2.95; W/W -/- 2.94 ± 0.83; n=6; p<0.001). Aortic rings from Flox/Flox Tie2 mice demonstrated impaired endothelium-dependant vasodilatation to ETB receptor selective agonists and acetylcholine but normal endothelium-independent vasodilatation. Recombination-mediated removal of exons 2 and 3 of the ETB receptor is sufficient to prevent expression of functional ETB receptors. The ‘floxed’ ETB receptor mouse thereby facilitates the cell type-specific down-regulation of ETB receptor expression in vivo. The EC ETB receptor plays an important role in the determination of blood pressure under normal physiological conditions. The mechanism underlying this effect may involve loss of EC ETB receptor-mediated vasodilatation or impaired clearance of ET-1 with a consequent increase in ETA receptor activity.
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Leslie, Stephen James. "The effect of endothelin A and endothelin B receptor ligands on the cardiovascular system of man." Thesis, University of Edinburgh, 2005. http://hdl.handle.net/1842/29221.
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ET-1 vasoconstricts in the skin microcirculation and it appears that endothelin converting enzyme (ECE) activity is present as big ET-1 also vasoconstricts. ECE and neutral endopeptidase (NEP) blockade both cause vasodilatation suggesting skin basal resting ET tone. ET-1 (1-31) is also a vasoconstrictor in the skin microcirculation. Plasma concentrations of ET-1(1-31) are not elevated in patients with CHF. ETARA improves systemic haemodynamics in patients with CHF while concomitant ETBRA attenuates this effect. In the isolated human myocardium ET is positively inotropic but there is no resting ET inotropy with no effect on basal twitch force with ETRA. In addition, ET attenuates beta-adrenergic activation in isolated human myocardium. In hypercholesterolaemia, forearm vascular effects are similar to those previously reported in healthy volunteers. Treatment with statin therapy for 8 weeks caused a trend towards an increase in ETA mediated vasodilatation. Conclusions: The novel finding that ET(1-31) is a vasoconstrictor in the skin microcirculation may represent a novel pathway of ET production. The haemodynamic benefits of selective ETARA over dual ETA/BRA is a unique finding with considerable importance and supports the development of selective ETARAs as clinical therapies in CHF. The finding of antagonism between the ET system and the beta-adrenergic stimulation may represent a protective adaptation in conditions where there beta-adrenergic stimulation is detrimental and there is activation of the ET system, such as CHF.
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Elez, Danka. "Production of recombinant human endothelin B receptor in different hosts and its subsequent solubilization and purification." [S.l.] : [s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=970794746.
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Kelland, Nicholas. "The role of the endothelial cell endothelin B receptor in cardiovascular function." Thesis, University of Edinburgh, 2007. http://hdl.handle.net/1842/1899.
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Endothelin-1 (ET-1) binds to endothelin A (ETA) and B (ETB) receptors on vascular smooth muscle cells, resulting in profound vasoconstriction and cellular proliferation. In contrast, activation of endothelial cell (EC) ETB receptors releases nitric oxide (NO) and prostacyclin (PGI2), which are anti-mitotic and mediate vasodilatation. ETB receptors are also responsible for the clearance of ET-1 from the circulation and renal ETB receptors contribute to sodium and water balance. Pharmacological blockade and genetic models featuring total ETB ablation, demonstrate salt sensitive hypertension. However, these do not allow the role of the EC ETB in cardiovascular homeostasis to be determined. Mice featuring loxP sites flanking exons 3 and 4 of the ETB gene (floxed ETB mice: FF/--) were crossed with Tie2-Cre mice (WW/Tie2-Cre), in which the expression of a Cre recombinase cDNA transgene is limited to EC, to generate EC-specific ETB down-regulated mice (FF/Tie2-Cre). Having demonstrated EC-specific down-regulation of ETB receptors using autoradiography, the role and relative contribution of the EC ETB to the regulation of systemic BP, to the clearance of ET-1 from the plasma, as well as to the development of pulmonary arterial hypertension were investigated. Autoradiography revealed significant down-regulation of ETB in EC-rich tissues such as lung of FF/Tie2-Cre animals (8 ± 3 amol.mm-2) compared to controls (80 ± 21 amol.mm-2) (n=4; p<0.05). Levels of ETA expression were preserved despite higher concentrations of plasma ET-1 in the FF/Tie2-Cre samples (12.4 ± 3.0 pg.ml-1) compared to controls (3.0 ± 0.8 pg.ml-1) (n=6; p<0.001). Using radiotelemetry, mean arterial blood pressure of FF/Tie2 mice was not significantly different to that of FF/- controls on low salt (FF/Tie2-Cre: 122.7 ± 1.52 mmHg, n=10; FF/--: 125.7 ± 0.58 mmHg, n=12), normal salt (FF/Tie2-Cre: 133.8 ± 4.0 mmHg, n=10; FF/--: 131.5 ± 3.33 mmHg, n=12) or high salt diet (FF/Tie2-Cre: 149.2 ± 2.71 mmHg, n=10; FF/--: 143.9 ± 2.97 mmHg, n=12). Similarly no differences in SBP, DBP or HR were seen between genotypes. The clearance of an intravenous bolus of radiolabelled ET-1 was significantly impaired in FF/Tie2-Cre mice (0.054 ± 0.006 ml.sec-1) compared to control mice (0.175 ± 0.032 ml.sec-1) (n=5; p<0.01). ETB blockade of control mice reduced ET-1 clearance to that of untreated FF/Tie2-Cre animals (n=4). Two weeks of hypobaric hypoxia induced an exaggerated increase in systolic right ventricular pressure in FF/Tie2-Cre mice (34.4 ± 1.2 mmHg, n=10) compared with FF/-- mice (24.6 ± 1.4mmHg, n=10; p<0.05), associated with an increased right ventricular/ left ventricular + septum ratio in FF/Tie2-Cre mice (normoxia: 0.224 ± 0.009; hypoxia: 0.285 ± 0.017; p<0.01), but not in FF/-- mice. Hypoxia increased the percentage of remodeled vessels in FF/-- mice (normoxia: 5.6 ± 0.6%; hypoxia: 11.4 ± 0.6%; n=6; p<0.001), and this was augmented in FF/Tie2-Cre mice (normoxia: 7.1 ± 0.5%; hypoxia: 18.5 ± 1.2%; n=6; p<0.001). The EC ETB receptor does not play a significant role in the BP response to salt, suggesting that ETB signalling on other cell types is responsible for ETB mediated natriuresis. However, the EC ETB receptor is crucial to the elimination of ET-1 from the circulation and is protective against the development of pulmonary arterial hypertension, most likely by preventing remodeling of small pulmonary arteries.
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Wu, Sumin [Verfasser]. "Structural and functional basis of Endothelin-1 type A receptor (ETAR) activation / Sumin Wu." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2019. http://d-nb.info/1179779118/34.
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Lowenstein, Marcia. "Interactions between Endothelin Receptor B and Transcription Factors Sox10 and Pax3 in the Melanocyte Lineage." FIU Digital Commons, 2009. http://digitalcommons.fiu.edu/etd/117.
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Genetic interactions that underlie developmental processes such as cell differentiation and pattern formation are complex and difficult to elucidate. Neural Crest (NC) cells and their derivatives offer an optimal system in which to probe for these complex interactions as they acquire different cell fates and constitute a variety of structures. The transcription factors Sox10 and Pax3 as well as the transmembrane receptor Endothelin receptor b (Ednrb) are temporally and spatially co-expressed early in NC cells and mutations in these genes lead to similar hypopigmentation phenotypes due to a reduced number of NC-derived melanocyte precursors, the melanoblasts. The goal of this study was to establish whether Sox10 and Ednrb or Pax3 and Ednrb interact to promote normal murine melanocyte development. Crosses of Sox10 or Pax3 with Ednrb heterozygous mutants showed that the double heterozygous hypopigmentation phenotype was significantly more pronounced than phenotypes of single heterozygotes, implying that a synergistic interaction exists between Sox10 and Ednrb and Pax3 and Ednrb. This interaction was further explored by the attempt to rescue the Sox10 and Pax3 hypopigmentation phenotypes by the transgenic addition of Ednrb to melanoblasts. Pigmentation was completely restored in the Sox10 and partially restored in the Pax3 mutant mice. The comparison of the number of melanoblasts in transgenic and non-transgenic Sox10 mutant embryos showed that the transgenic rescue occurred as early as E11.5, a critical time for melanoblast population expansion. Cell survival assays indicated that the rescue was not due to an effect of the transgene on melanoblast survival. A novel phenotype arose when studying the interaction between Ednrb and Pax3. Newborns appeared normal but by 3.5 weeks of age, the affected pups were smaller than normal littermates and developed a dome-shaped head; some also developed thoracic kyphosis. Affected pups were dead by 4 weeks of age: 80% were Pax3Sp/+ and 75% were female. When compared to normal littermates, affected mice had brains with enlarged 4th ventricles and more glia while skeletal staining showed kyphosis, wider rib cages and pelvic differences. An epistatic interaction resulting from the mixing of genetic backgrounds that is exacerbated in the presence of Pax3 heterozygosity is suspected.
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Neder, Thomas Harry [Verfasser], and Charlotte [Akademischer Betreuer] Wagner. "The endothelin-A and endothelin-B receptor as potential factors to control synthesis and secretion of renin / Thomas Harry Neder ; Betreuer: Charlotte Wagner." Regensburg : Universitätsbibliothek Regensburg, 2018. http://d-nb.info/1155360753/34.
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Chin, Nikeisha L. "The Role of Endothelin 3 in Melanoma Progression and Metastasis." FIU Digital Commons, 2015. http://digitalcommons.fiu.edu/etd/2286.
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Endothelin receptor b (Ednrb) and its ligand Endothelin 3 (Edn3) have been implicated in melanoma. Several studies have shown an upregulation of EDNRB and EDN3 at both the protein and mRNA levels, as melanoma becomes more aggressive. This study investigated the putative role played by Edn3 over-expression in melanoma progression and angiogenesis in vivo. We crossed Tg(Grm1)Epv transgenic mice that aberrantly express metabotropic glutamate receptor1 under the Dopachrome tautomerase promoter, leading to spontaneous melanocytic lesions in the ears and tails that do not metastasize, with transgenics that overexpress Edn3 under the Keratin 5 promoter (K5-Edn3) or overexpress Ednrb in melanocytes (Tg(Ednrb)1Lk). In both the Tg(Grm1)Epv/K5-Edn3 and Tg(Grm1)Epv/Tg(Ednrb)1Lk mice, tumors appeared earlier and grew significantly larger and faster when compared to Tg(Grm1)Epv mice. Approximately eighty-one percent of Tg(Grm1)Epv/ K5-Edn3 mice and 76% of Tg(Grm1)Epv/Tg(Ednrb)1Lk mice had pigmented lesions in distant organs such as the lung and brain. Real-Time PCR analysis showed higher expression levels of genes involved in cell-cell and cell-matrix interactions and angiogenesis in lesions of Tg(Grm1)Epv/K5-Edn3 when compared to controls. Considering the rapid tumor growth rate of in the Tg(Grm1)Epv/K5-Edn3 mice, differences in the angiogenic response compared to control mice were investigated. Immunofluorescence analysis with the endothelial cell marker CD31 showed that there were more endothelial cells per tumor area in the Tg(Grm1)Epv/K5-Edn3 mice than the controls. Proteome analysis showed that the Dct-Grm1/K5-Edn3 mice had significant increases in other angiogenic related genes such as Angiogenin, CXCL 16 and Endoglin, when compared to controls, while real time PCR analysis of tail tumors also showed higher expression levels of angiogenic related genes such as Hif-1α. The results of this study showed that the EDNRB/EDN3 axis is sufficient to alter the kinetics of melanocytic tumors’ progression, lead them to a fully malignant state, and increase the tumor angiogenic response.
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Zheng, Zhong. "ROLE OF SCAVENGER RECEPTOR CLASS B TYPE I IN THYMOPOIESIS." UKnowledge, 2014. http://uknowledge.uky.edu/nutrisci_etds/12.
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T cells, which constitute an essential arm in the adaptive immunity, complete their development in the thymus through a process called thymopoiesis. However, thymic involution can be induced by a couple of factors, which impairs T cell functions and is slow to recover. Therefore, understanding how thymopoiesis is regulated may lead effort to accelerate thymic recovery and improve immune functions in thymocyte-depleted patients. In this project, we identified scavenger receptor BI (SR-BI), a high density lipoprotein (HDL) receptor, as a novel modulator in thymopoiesis. In mice, absence of SR-BI causes a significant reduction in thymus size after puberty and a remarkable decrease in thymic output. Consequently, SR-BI-null mice show a narrowed naïve T cell pool in the periphery and blunted T cell responses, indicating that the impaired thymopoiesis due to SR-BI deficiency leads to compromised T cell homeostasis and functions. The impaired thymopoiesis of SR-BI-null mice is featured by a significant reduction in the percentage of earliest T progenitors (ETPs) but unchanged percentages of other thymocyte subtypes, suggesting that SR-BI deficiency causes a reduction in progenitor thymic entry. Further investigations reveal that SR-BI deficiency impairs thymopoiesis through affecting bone marrow progenitor thymic homing without influencing the lymphoid progenitor development in bone marrow. Importantly, SR-BI-null mice exhibit delayed thymic recovery after sublethal irradiation, indicating that SR-BI is also required for thymic regeneration. Using bone marrow transplantation models, we elucidate that it is non-hematopoietic rather than hematopoietic SR-BI deficiency that results in the defects in thymopoiesis. However, SR-BI deficiency-induced hypercholesterolemia is not responsible for the impaired thymopoiesis. Using adrenal transplantation models, we found that absence of adrenal SR-BI is responsible for the impaired thymopoiesis, as shown by that adrenalectomized mice transplanted with SR-BI-null adrenal gland display reduced thymus size, decreased percentage of ETPs and delayed thymic regeneration compared with those transplanted with wild-type adrenal. Altogether, results from this study elucidate a previously unrecognized role of SR-BI in thymopoiesis. We reveal that SR-BI expressed in adrenal gland is critical in maintaining normal T cell development and enhancing thymic regeneration, providing novel links between adrenal functions and T cell development.
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Parsons, Tina. "Receptor-mediated iron and haem transport in Haemophilus." Thesis, University of Nottingham, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.282581.
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Mulcahy, Jane Victoria. "Human scavenger receptor class B, type II (SR-BII) and cellular cholesterol efflux." Thesis, University College London (University of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.396278.
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Christjanson, Lisa J. "Transcriptional regulatory elements in the interleukin-8 receptor type B (IL-8RB) proximal promoter." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp05/mq21038.pdf.
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Ai, Junting. "THE ROLE OF SCAVENGER RECEPTOR CLASS B TYPE I-REGULATED INDUCIBLE GLUCOCORTICOIDS IN SEPSIS." UKnowledge, 2014. http://uknowledge.uky.edu/nutrisci_etds/14.
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Sepsis claims over 215,000 lives in the US annually. Inducible glucocorticoids (iGC) is produced during sepsis. However, the precise effects of iGC in sepsis remain unclear due to a lack of appropriate animal models. Glucocorticoid (GC) insufficiency is associated with a marked increase in mortality and occurs in 60% of severe septic patients. Yet the conclusion of GC therapy on septic patients is still controversial.
Scavenger receptor class B type I (SR-BI) in the adrenal mediates the selective uptake of cholesteryl ester from lipoproteins for GC synthesis. SR-BI-/- mice completely lack iGC during sepsis and are highly susceptible to septic death, which presents SR-BI-/- mice as a GC insufficient model. However, SR-BI-/- mice display multiple defects contributing to septic death, making it difficult to study iGC by using these mice. Therefore, we utilized adrenal-specific SR-BI-/- mice (ADR-T SR-BI-/-) generated by adrenal transplantation. As expected, the ADR-T SR-BI-/- mice failed to generate iGC under cecal ligation and puncture (CLP)-induced sepsis and showed a significantly higher mortality than the control mice, demonstrating that iGC is essential for preventing septic death. High blood urea nitrogen (BUN) was observed in the ADR-T SR-BI-/- mice but not in the control mice in CLP, indicating that iGC protects kidney injury in sepsis. Plasma IL-6 was remarkably higher in the ADR-T SR-BI-/- mice than the control mice, demonstrating an anti-inflammatory effect of iGC in sepsis. The ADR-T SR-BI-/- mice also displayed significantly lower phagocytic activity of monocytes and neutrophils in the blood and lower activation of T cells in the spleen compared to the control mice in CLP, suggesting that iGC is immunomodulatory in sepsis. Low-dose GC supplementation significantly improved the survival of SR-BI-/- mice in CLP, but did not increase the survival rate of SR-BI+/+ mice in CLP, indicating that GC supplementation improves the survival specifically in mice with adrenal insufficiency.
Overall, we revealed that iGC is essential for sepsis survival. iGC prevents kidney damage, modulates inflammatory responses and exerts immunomodulatory functions in sepsis. GC supplementation specifically improves survival of individuals with adrenal insufficiency in sepsis.
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Arandhara, Victoria. "The role of scavenger receptor class B type I in hepatitis C virus infection." Thesis, University of Nottingham, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.430304.
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Pino, Javier. "Transgneic Endothelin 3 Regulates Murine Pigment Production and Coat Color." FIU Digital Commons, 2017. https://digitalcommons.fiu.edu/etd/3533.
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Pigmentation plays a protective role against damage caused by ultraviolet (UV) irradiation. Humans with fair skin and light hair have a higher susceptibility to UV-induced DNA damage that can lead to the development of skin cancers. The melanocytes found in the skin and hair follicles depend on different signaling molecules for their proper development and pigment production. α-Melanocyte Stimulating Hormone (α-msh) binds to the Melanocortin 1 receptor (Mc1r) to regulate pigment production and the switch between eumelanin and pheomelanin. Lethal yellow mice (Ay) overexpress the agouti signaling protein, which inhibits the binding of α-msh, resulting in a yellow coat color phenotype. Endothelin 3 (Edn3) encodes for a ligand involved in melanocyte development by regulating the differentiation, proliferation and migration of melanocyte precursors. A tetracycline inducible transgenic mouse in which Edn3 was placed under the keratin 5 promoter (K5-tTA;TRE-Edn3-lacZ) displays a hyperpigmentation phenotype due to the accumulation of melanocytes in the skin and an increase in hair pigment. Comparative analysis of dorsal hairs from Ay and Ay; K5-tTA;TRE-Edn3-lacZ mice using high performance liquid chromatography showed that transgenic Edn3 expression significantly increased both eumelanin and pheomelanin. No significant difference in the number of follicular melanocytes between Edn3 transgenic and non-transgenic mice was evidenced by immunofluorescence using an antibody against Tyrosinase related protein 1. Gene expression analysis of hair follicles showed that Edn3 upregulates the expression of melanogenic genes. Deactivation of transgenic Edn3 is possible with doxycycline (dox) treatment. To test if transgenic Edn3 expression is required to rescue and maintain a dark pigmentation phenotype in Ay mice, dox was administered during embryonic and postnatal development to manipulate transgenic Edn3 expression. Results showed that transgenic Edn3 expression is required to maintain a dark pigmentation phenotype after birth but is independent of a developmental requirement. Transgenic Edn3 expression in Mc1re/e mice also resulted in a darkened coat color. Our results indicate that the paracrine expression of Edn3 from keratinocytes is capable of generating and maintaining a dark coat color by the regulation of melanogenic genes independent of Mc1r signaling. The results of this study may open new approaches to the treatment of hypopigmentation disorders.
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Nakao, Kazuhiro. "ENDOTHELIUM-DERIVED C-TYPE NATRIURETIC PEPTIDE CONTRIBUTES TO BLOOD PRESSURE REGULATION BY MAINTAINING ENDOTHELIAL INTEGRITY." 京都大学 (Kyoto University), 2017. http://hdl.handle.net/2433/225500.
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Noubani, Alfred. "B-type natriuretic peptide receptor expression and activity is hormonally regulated in rat ovarian cells." Thesis, McGill University, 1999. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=33432.
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Natriuretic peptides form a family of structurally-related peptides known to regulate salt and water homeostasis and to cause vasodilation. Synthesis of atrial (ANP), brain (BNP), and C-type (CNP) natriuretic peptides occurs mainly in the heart and brain and has been identified recently in the female reproductive tract. The expression of ANP and CNP, as well as their cognate guanylyl cyclase receptors (NPR-A and NPR-B, respectively), have been detected in the rat ovary.We have shown previously that the expression of the natriuretic peptides and their receptors, in the rat ovary, is modulated by the estrous cycle. Since estrogen and the gonadotropins (luteinizing hormone (LH) and follicle-stimulating hormone (FSH)) are important regulators of follicular development and ovarian function we hypothesized that expression of the natriuretic peptide system is modulated by these hormones. In order to test this hypothesis, the expression of the natriuretic peptide system (peptide and receptor) was evaluated in ovarian cells (granulosa and residual tissue cells) obtained from immature female rats treated with either diethylstilbestrol (DES), an estrogen analogue, or equine chorionic gonadotropin (eCG), a gonadotropin which possesses both LH and FSH activity. (Abstract shortened by UMI.)
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Fenske, Sara Anne. "Tissue specific regulation of the high density lipoprotein (HDL) receptor, scavenger receptor Class B, Type I (SR-BI) by the scaffold protein PDZK1." Thesis, Massachusetts Institute of Technology, 2008. http://hdl.handle.net/1721.1/45805.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, September 2008.Includes bibliographical references.
PDZK1 is a four PDZ-domain containing cytoplasmic adaptor protein that binds the Cterminus of the high-density lipoprotein (HDL) receptor SR-BI. Abolishing PDZK1 expression in PDZK1 knockout (KO) mice leads to a post-transcriptional, tissue-specific decrease in SR-BI protein level and an increase in total plasma cholesterol carried in abnormally-large HDL particles. A greater than 95% decrease in SR-BI expression levels is observed in the livers of PDZK1 KO mice. The mechanism behind this tissue-specific regulation of SR-BI expression is unclear. PDZK1 comprises multiple structural features that, aside from the first PDZ domain, which binds SR-BI, are not known to interact with SR-BI. It seems probable that these structures (three PDZ domains, at least one phosphorylation site on the C- terminal tail, and a putative PDZ-binding motif at its C-terminus) might interact with other cellular components to influence hepatic SR-BI expression. This thesis explores the role of PDZK1's structural features in the PDZK1-dependent regulation of hepatic SR-BI through the hepatic expression of PDZK1 and various truncation and point mutants of PDZK1 in wild-type (WT) and PDZK1 KO mice. These studies demonstrated that overexpression of the first PDZ domain of PDZK1 can affect hepatic SR-BI abundance and localization in both WT and PDZK1 KO mice, but was not sufficient to restore normal SR-BI function in PDZK1 KO mice. Overexpression of the first three domains of PDZK1 in PDZK1 KO mice was able to partially restore cell-surface localization and function of hepatic SR-BI, but was not able to fully restore SR-BI abundance, localization and abundance.
(cont.) Overexpression of full-length PDZK1 or a mutant missing the C-terminal PDZ-binding motif of PDZK1 in PDZK1 KO mice was sufficient to restore normal SR-BI abundance and activity. Therefore, we conclude that some structural feature of PDZK1 between the PDZ3 domain and the C-terminal PDZ-binding motif is required for normal SR-BI expression and. thus, function. It is possible that this feature may be the PDZ4 domain of PDZK1, as preliminary data suggests that overexpression of the four PDZ domains of PDZK1 (missing the C-terminal tail) might be able to fully restore hepatic SR-BI function.
by Sara Anne Fenske.
Ph.D.
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Darrah, Rebecca J. "Genetic Modifiers of Cystic Fibrosis Pulmonary Disease." Case Western Reserve University School of Graduate Studies / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=case1270133199.
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Bwanali, Jessica Atupele. "Identification of hepatitis C virus E2 glycoprotein binding determinants on human scavenger receptor class B type 1." Thesis, University of Nottingham, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.537621.
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Zhou, Jie. "Genetic polymorphisms of type I interferon receptor 1 affect the susceptibility to chronic HBV infection association analysis and mechanistic investigation /." Click to view the E-thesis via HKUTO, 2007. http://sunzi.lib.hku.hk/hkuto/record/B38722951.
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周婕 and Jie Zhou. "Genetic polymorphisms of type I interferon receptor 1 affect the susceptibility to chronic HBV infection: association analysis and mechanistic investigation." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2007. http://hub.hku.hk/bib/B38722951.
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Eroglu, Ezgi. "Association Between Gamma Aminobutyric Acid (gaba) Type B Receptors Gene Polymorphisms And Idiopathic Generalized Epilepsy." Master's thesis, METU, 2012. http://etd.lib.metu.edu.tr/upload/12614056/index.pdf.
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Epilepsy is neurological disorder affecting 0.5 to 1% of the population all around the world. It is characterized by the seizures, which are the sudden alterations of behavior due to a temporary change in electrical functioning of the brain. Idiopathic generalized epilepsy (IGE) accounts for one-fifth of all the other epilepsy types, and several gene mutations were identified as the causes of IGE. In general, voltage-gated and ligand-gated ion channel mutations are linked with seizure formation. Gamma amino butyric acid (GABA), the most important inhibitory neurotransmitter of the central nervous system, and its receptors are commonly mentioned in the pathophysiology of epilepsies. Decrease in the inhibitory effect of GABA in neurons causes epileptic discharges resulting in seizure development.
The study population consisted of a total of 176 idiopathic generalized epilepsy (IGE) patients, 83 subjects having psychogenic non-epileptic seizures (PNES), 86 non-epileptic control subjects from Turkey. Total blood samples were obtained from Gülhane Military Medical Academy Hospital Neurology Department, Ankara. There was no statistically difference between the patient and control groups in terms of age. Genomic DNA isolations were performed and genotyping of G1465A and C59T polymorphisms of GABAB1 gene
rs1999501, rs967932, rs3780428 and rs944688 polymorphisms of GABAB2 gene were determined by PCR-RFLP technique. In this study, GABAB1 G1465A polymorphic allele was not observed in Turkish population. For GABAB1 C59T polymorphism, polymorphic allele frequencies were found as 0.097 in IGE patients
0.072 in PNES subjects and 0.105 in non-epileptic control subjects. No significant difference is identified for C59T polymorphism in all three groups. Four SNPs of GABAB2 were studied
rs967932 was found to increase the risk of IGE 3.6-fold (P=0.031) compared to PNES subjects, polymorphic allele frequencies were found as 0.060 in IGE patients
0.018 in PNES subjects and 0.035 in non-epileptic control subjects. For rs1999501 polymorphism, polymorphic allele frequencies were found as 0.077 in IGE patients
0.048 in PNES subjects and 0.093 in non-epileptic control subjects. For rs3780428 polymorphism, polymorphic allele frequencies were found as 0.267 in IGE patients
0.235 in PNES subjects and 0.256 in non-epileptic control subjects. For rs944688 polymorphism, polymorphic allele frequencies were found as 0.196 in IGE patients
0.260 in PNES subjects and 0.227 in non-epileptic control subjects. No significant difference was identified for rs1999501, rs3780428 and rs944688 polymorphisms among IGE patients, PNES subjects and non-epileptic control groups. IGE risk was 6.54-fold higher for subjects having combined GA genotype for rs967932 and GG genotype for rs3780428 when compared with PNES subjects (P=0.042). The combination of CC genotype for rs1999501, GG genotype for rs967932 and TT genotype for rs944688 had around 9-fold protective effect against IGE when both compared with PNES subjects (P=0.038) and non-epileptic control subjects (P=0.041).
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Stanton, Suzanne Louise. "Homology Modeling and Molecular Docking of Antagonists to Class B G-Protein Coupled Receptor Pituitary Adenylate Cyclase Type 1 (PAC1R)." ScholarWorks @ UVM, 2016. http://scholarworks.uvm.edu/graddis/624.
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Recent studies have identified the Class B g-protein coupled receptor (GPCR) pituitary adenylate cyclase activating polypeptide type 1 (PAC1R) as a key component in physiological stress management. Over-activity of neurological stress response systems due to prolonged or extreme exposure to traumatic events has led researchers to investigate PAC1R inhibition as a possible treatment for anxiety disorders such as post-traumatic stress disorder (PTSD). In 2008, Beebe and coworkers identified two such small molecule hydrazide antagonists and a general pharmacaphore for PAC1R inhibition. However, a relative dearth of information about Class B GPCRs in general, and PAC1R in specific, has significantly hindered progress toward the development of small molecule antagonists of PAC1R. The recent crystallization of the homologically similar glucagon receptor (GCGR) by Siu and coworkers in 2013, also a Class B receptor, has provided an experimentally resolved template from which to base computationally derived models of PAC1R.
Initially, this research was focused towards synthesizing small molecule antagonists for PAC1R which were to be biologically screened via a qualitative western blot assay followed by a radioisotope binding assay for those hydrazides exhibiting down-stream signaling inhibitory capabilities. However, the resolution of the GCGR crystal structure shifted research objectives towards developing a homology model of PAC1R and evaluating that computationally created model with Beebe's known small molecule antagonists. Created using academic versions of on-line resources including UniProtKB, Swiss-Model and Maestro, a homology model for PAC1R is presented here. The model is validated and evaluated for the presence of conserved Class B GPCR residues and motifs, including expected disulfide bridges, a conserved tyrosine residue, a GWGxP motif, a conserved glutamic acid residue and the extension of the transmembrane helix 1 (TM1) into the extra-cellular domain.
Having determined this virtual PAC1R an acceptable model, ligand docking studies of known antagonists to the receptor were undertaken using AutoDock Vina in conjunction with AutoDock Tools and PyMol. Computational docking results were evaluated via comparison of theoretical binding affinity results to Beebe's experimental data. Based on hydrogen bonding capabilities, several residues possibly key to the ligand-receptor binding complex are identified and include ASN 240, TYR 241 and HIST 365. Although the docking software does not identify non-bonding interactions other than hydrogen-bonding, the roles of additional proposed binding pocket residues are discussed in terms of hydrophobic interactions, π-π interactions and halogen bonding. These residues include TYR 161, PHE 196, VAL 203, PHE 204, ILE 209, LEU 210, VAL 237, TRP 297, PHE 362 and LEU 386. Although theoretical in nature, this reported homology modeling and docking exercise details a proposed binding site that may potentially further the development of drugs designed for the treatment of PTSD.
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Twiddy, Alexis. "An investigation of cholesterol pathways in castration-resistant prostate cancer : the role of scavenger receptor class B type I (SR-BI)." Thesis, University of British Columbia, 2011. http://hdl.handle.net/2429/39383.
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Background. Scavenger Receptor Class B Type I (SR-BI) facilitates influx of cholesterol to the cell from lipoproteins in the circulation. This influx of cholesterol is important for many cellular functions, including synthesis of androgens. Castration-resistant prostate cancer tumors are able to synthesize androgens de novo in order to supplement the loss of exogenous sources often as a result of androgen deprivation therapy. By removing a source of cholesterol, silencing of SR-BI may impact the ability of prostate cancer cells, particularly those of castration-resistant state, to maintain the intracellular supply of androgens.
Methods. SR-BI expression was knocked down in LNCaP (androgen-dependent) and C4-2 (castration-resistant) cells using small interfering RNA. The effect of down-regulation of SR-BI on cell toxicity, cell viability, and expression of various proteins was examined using a LDH assay, a MTS assay and western blotting in both cell types. In addition, cholesterol synthesis activity was measured using the radiolabeled precursor, ¹⁴C-acetate and cellular cholesterol, testosterone and PSA concentrations were assessed using fluorometric and colorometric assays.
Results. Basal SR-BI and HSL protein expression was higher in C4-2 cells than LNCaP cells. Silencing of SR-BI expression by greater than 85% reduced PSA secretion in LNCaP and C4-2 SRBI-KD cells by 55% and 58% compared to negative control cells, respectively. SR-BI-KD C4-2 cells demonstrated significantly reduced cell viability (>25%) compared the NC cells as well as an increased cholesterol synthesis 6 days post-transfection.
Conclusions. The down-regulation of SR-BI significantly impacted PSA production of both prostate cancer cell lines, as well as the viability of C4-2 cells in the presence and absence of HDL. Although corresponding changes in cholesterol and testosterone concentrations were not observed, the data suggest that silencing SR-BI and thereby reducing cholesterol influx impacts cholesterol pathways, as evidenced by a compensatory up-regulation of de novo cholesterol synthesis. This may affect substrate availability to the androgen synthesis pathway or may implicate a separate role of SR-BI in prostate cancer cells.
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Biétrix, Florence. "Etude l'absorption intestinale de lipides dans un modèle de souris trangéniques surexprimant, le scavenger receptor class B type I : sr-bi." Toulouse 3, 2006. http://www.theses.fr/2006TOU30273.
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Il est actuellement admis que le cholestérol d'origine alimentaire contribue fortement aux taux de cholestérol circulant dans le sang, un facteur de risque associé au développement des maladies cardiovasculaires. Néanmoins, les processus d'absorption intestinale du cholestérol ne sont pas encore complètement élucidés. Le Scavenger Receptor Class B Type I : (SR-BI) est un acteur majeur du transport du cholestérol dans différents tissus. Il est également présent au niveau de l'intestin où son rôle dans la captation du cholestérol reste controversé. Afin d'étudier sa participation dans l'absorption intestinale du cholestérol, nous avons généré des souris surexprimant cette protéine au niveau de l'intestin à l'aide de l'« enhancer » de l'apolipoprotéine CIII couplé au promoteur de l'apolipoprotéine AIV de spécificité intestinale. Des souris gavées avec un mélange lipidique contenant du [14C]-cholestérol et [3H]-triglycérides (TG) présentent 4 h après le gavage une augmentation importante (3 fois) de la radioactivité plasmatique associée au cholestérol et aux TG, indiquant que SR-BI est capable de favoriser la captation du cholestérol mais aussi des TG alimentaires (ou de leurs produits d'hydrolyse). L'analyse massique confirme une augmentation de 20 % des TG plasmatiques chez les souris SR-BI transgéniques par rapport aux contrôles. Par contre, la surexpression de SR-BI induit une diminution de 50 % du taux massique de cholestérol plasmatique sans variation du taux d'apolipoprotéine AI (ApoA-I), suggérant une réponse adaptative particulière. De plus, des souris transgéniques de fonds génétiques différents (B6D2 vs C57/Bl6) présentent des variations importantes des taux de cholestérol plasmatique sans variation du taux d'Apo-AI ou de l'expression de SR-BI dans l'intestin ou le foie suggérant des modulations de gènes différentes en fonction de leur fond génétique. La vitamine E est un micronutriment essentiel, solubilisée dans l'intestin en même temps que le cholestérol sous la forme de micelles mixtes afin d'être absorbé. Nous avons montré par des techniques de gavages avec du g tocophérol (forme non métabolisable de la vitamine E), que son absorption intestinale était augmentée chez les souris surexprimant SR-BI dans l'intestin. Ces résultats suggèrent l'implication de ce transporteur dans l'absorption intestinale des nutriments liposolubles et permettent d'envisager son rôle dans leur biodisponibilité. . .
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Sandqvist, Anna. "Vardenafil and methylarginines in pulmonary hypertension." Doctoral thesis, Umeå universitet, Klinisk farmakologi, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-113903.
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Background: Pulmonary hypertension (PH) is a rare condition characterized by endothelial dysfunction and vascular remodelling, leading to increased pulmonary vascular resistance (PVR) and right ventricular heart failure. Endothelial dysfunction is associated with an imbalance between vasoconstrictor compounds, such as endothelin and thromboxane A2, and vasodilator compounds, such as prostacyclin and nitric oxide (NO). Asymmetric dimethylarginine (ADMA), a methyl derivate of L-arginine, inhibits synthesis of NO. Vardenafil, a phosphodiesterase type 5 inhibitor (PDE5-inhibitors), causes vasodilation through the NO/cGMP pathway. Aim: This thesis investigates the pharmacological effects and diagnostic utility of vardenafil in PH patients. In addition, to evaluate the change of L-arginine and dimethylarginines before and during PAHspecific therapy in PAH patients compared to patients with left ventricular heart failure (LVHF) and healthy subjects. Methods: The pharmacokinetics and hemodynamic effects of vardenafil were examined during right heart catheterization (RHC) in 16 PH patients and plasma concentrations were measured for up to nine hours after oral administration. In 20 PH patients, acute vasoreactivity test with vardenafil was performed during RHC. Hemodynamic responses were recorded, responders were defined and followed for up to seven years. Additionally, plasma ADMA, symmetric dimethylarginine (SDMA), L-arginine, L-citrulline and L-ornithine levels before and after PAH drug treatment were monitored in 21 PAH patients and compared to values measured in 14 LVHF patients and 27 healthy subjects. Results: Vardenafil concentrations increased rapidly to maximum plasma concentration (tmax 1h) and elimination half-life was 3.4 h. Patients co-medicated with bosentan had reduced vardenafil concentration. Significant acute hemodynamic responses were observed for mean pulmonary artery pressure (mPAP) (p<0.001), pulmonary vascular resistance (PVR) (p<0.001), cardiac output (CO) (p=0.015), cardiac index (CI) (p=0.010), systemic vascular resistance (SVR) (p<0.001) and PVR/SVR (p=0.002) and were related to plasma vardenafil concentrations. PAH patients had significantly higher ADMA and SDMA levels and significantly lower L-arginine levels and L-arginine/ADMA ratio compared with healthy subjects (p<0.001). L-arginine was also lower in PAH patients compared to patients with LVHF (p<0.05). WHO functional class and six minutes walking distance (6MWD) correlated to Larginine and L-arginine/ADMA ratio in PAH at baseline (p<0.05). At follow-up, patients on mono- or combinationtherapy with endothelin receptor antagonists (ERA) had lower ADMA levels than patients without ERA (p<0.05). In contrast, patients on PDE5-inhibitors had higher ADMA levels compared to patients without PDE5-inhibitors (p<0.05). Conclusion: Vardenafil is safe in acute vasoreactivity test in PH patients. Cardiopulmonary hemodynamic response was related to plasma drug concentrations. There was a high inter-individual variability of vardenafil pharmacokinetics and co-medication with bosentan caused a pharmacokinetic drug interaction. Baseline L-arginine and dimethylarginines levels were different in PAH patients compared to LVHF patients and healthy controls. PAH-specific treatment influenced L-arginine and dimethylarginines. Our data suggest that L-arginine might be useful for differentiating PAH from LVHF, and L-arginine/ADMA ratios were related to the severity of PAH and might be useful for follow-up evaluations of PAH patients.
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Chen, Xiaochuan. "Chronic Norepinephrine Suppression Induces a Compensatory B-Cell Adaptation that Enhances Insulin Secretion after Alleviation of the Catecholamine Inhibition in Fetal Sheep." Diss., The University of Arizona, 2012. http://hdl.handle.net/10150/238671.
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Placental insufficiency-induced intrauterine growth restriction (IUGR) increases risk of mortality and morbidity in newborn infants and domestic animals. IUGR fetuses are typically exposed to prolonged hypoxemia, hypoglycemia, and hypercatecholaminemia, which results in perinatal pancreatic β-cell dysfunction. Recent evidence indicates that chronic exposure to norepinephrine in utero suppresses insulin secretion through α2-adrenergic receptors (ARs), but if the adrenergic actions are blocked compensatory hyper insulin secretion response is observed in the IUGR sheep fetus. In the current studies, we demonstrate that chronic NE exposure alone can produce the compensatory enhancement of β-cell responsiveness following termination of a chronic NE infusion. In the fetus NE was continuously infused at 1-4 μg/min for seven days starting at 131 days of gestational age (term = 145 days). During treatment, NE infused fetuses had higher (P < 0.05) plasma NE concentrations and lower (P < 0.01) insulin concentrations than vehicle infused control fetuses. Glucose stimulated insulin secretion (GSIS), which measures β-cell function, prior to NE treatment was not different between treatments. However, insulin concentrations during hyperglycemic steady state period of GSIS studies and area under the curve of glucose-potentiated arginine-induced insulin secretion were higher (P < 0.01) than control values and this augmentation was confirmed at 3 hours, 24 hours, and five days in NE-infused fetuses after discontinuing the infusion. Pancreatic islets isolated within 10 hours post NE infusion had lower (P < 0.05) mRNA expression of α1D (58%), α2A (43%), α2C (42%), α1 (67%) adrenergic receptors (ARs), and uncoupling protein 2 (40%) compared to islets from controls. Isolated islets from NE-infused fetuses 5 days after NE treatment had lower (P < 0.05) inhibitory responsiveness from NE and a greater (P < 0.05) maximal insulin release with glucose simulation in static incubations compared to controls. These findings show that following chronic NE exposure insulin secretion responsiveness was augmented and was coupled with desensitized adrenergic signaling. Moreover, this compensatory β-cell enhancement persists for days indicating chronic NE exposure permanently alters β-cell responsiveness.
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Midha, Ankur. "Determining the role of scavenger receptor class B type I as a source of cholesterol for de novo androgen synthesis in castration-resistant prostate cancer." Thesis, University of British Columbia, 2015. http://hdl.handle.net/2429/54366.
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Existing therapies for castration-resistant prostate cancer (CRPC) extend life and provide clinical benefit; however, patients develop therapeutic resistance. Persistent androgen signaling in CRPC is maintained in part by intratumoral steroidogenesis from the precursor cholesterol. The high density lipoprotein-cholesterol (HDL) receptor, scavenger receptor class B type I (SR-BI), is upregulated in CRPC models in vitro and in vivo. This thesis tests the hypothesis that depriving CRPC cells of HDL as a cholesterol source by silencing SR-BI will diminish de novo steroidogenesis and resultant androgen receptor-mediated signaling necessary for CRPC viability. The effects of SR-BI silencing were studied using CRPC C4-2 cells transfected with either Stealth RNAi duplexes targeting SR-BI (SRBI-KD) or Lo GC Negative Control (NC) duplexes. Cells cultured in androgen-depleted conditions for varying times post-transfection were assessed for SR-BI expression, prostate specific antigen (PSA) expression by chemiluminescence, cholesterol levels by fluorometry, and steroid levels by liquid-chromatography-mass spectrometry. HDL-uptake was measured by flow cytometry of the fluorescent cholesterol mimetic 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate (DiI-HDL). Cell cycle state was assessed by flow cytometry of propidium iodide DNA staining, while cell cycle markers were assessed by immunoblotting. Adaptive stress responses were assessed by immunoblotting for autophagy markers, as well by flow cytometry for senescence associated beta-galactosidase (SA-β-gal) using a fluorogenic substrate, 5-dodecanoylaminofluorescein di-β-D-galactopyranoside. SRBI-KD treatment reduced SR-BI levels by ~57% by 2 days and ~86% by 4 days post-transfection. This correlated with reduced DiI-HDL-uptake by 22%, reduced cellular testosterone levels two-fold, and reduced PSA secretion by 39% compared to NC cells. These changes were accompanied by reduced proliferation, G₁S cell cycle arrest, and a small, but measurable increase in cell death at 4 to 6 days post-transfection. Cell stress was evidenced by enhanced autophagy activity and induced stress marker expression while senescence was evidenced by increased SA-β-gal activity. These studies indicate that SR-BI silencing reduced DiI-HDL uptake which reduced cellular androgen content and androgen signaling, resulting in induction of an adaptive stress response characterized by cell cycle arrest, autophagy, senescence, and eventually death of these CRPC cells. The data presented herein provide support for SR-BI as a cholesterol source for androgen synthesis in CRPC cells.Pharmaceutical Sciences, Faculty of
Graduate
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Bajpai, Saurabh. "ROLE OF HEPATIC CHOLESTEROL ESTER HYDROLASE (CEH) IN HYDROLYZING CHOLESTEROL ESTERS (CE) DELIVERED VIA SR-BI (SCAVENGER RECEPTOR CLASS B TYPE I) AND SR-BII." VCU Scholars Compass, 2009. http://scholarscompass.vcu.edu/etd/1711.
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Reduction of cholesterol ester (CE) from lipid burden lesion-associated macrophage foam cells has been shown to reduce plaque volumes. Hydrolysis of CE to free cholesterol (FC) in macrophages is an essential step for removal of CE from the macrophage and its transport to the liver by high density lipoprotein (HDL) for further metabolism. Since CE must again be hydrolyzed into FC in the liver catalyzing this hydrolysis, it becomes imperative to find the identity of these enzymes. In this study the role of key enzyme in catalyzing the hydrolysis of CE to FC, neutral cholesterol ester hydrolase (CEH) was evaluated. Further, ability of this CEH to hydrolyze CE delivered via scavenger receptor BI (SR-BI) or SR-BII was also monitored. CE hydrolysis and FC efflux were monitored from cells transfected with CEH expression vector. No significant difference was noted in either the intracellular CEH activity or FC efflux between cells transfected with an empty vector or a CEH expression vector. Further no difference was seen when experiments were repeated with cells stably transfected with SR-BI or SR-BII. Future experiments with more optimization of the cells system used will be required to reach any conclusions on the role of CEH in hydrolyzing HDL-CE delivered via SR-BI/BII.
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Ifie, Eseoghene. "An investigation of Coxsackie and Adenovirus receptor in the human pancreatic beta cells." Thesis, University of Exeter, 2018. http://hdl.handle.net/10871/34559.
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Human pancreatic beta cells are susceptible to infection by enteroviruses, especially Coxsackie B viruses, and such infections could contribute to the development of Type 1 diabetes. Enteroviruses gain entry via cell surface receptors, one of which, the Coxsackie and Adenovirus receptor (CAR), is a transmembrane cell adhesion protein which serves as a key entry receptor for Coxsackie B viruses and is thought to be localised mainly within regions where contacts are formed between adjacent cells. CAR exists as at least 5 isoforms and this study has examined their expression profile and distribution in the human pancreas utilising; formalin-fixed paraffin-embedded pancreatic sections from non-diabetic individuals, type 1 diabetes patients and a human tissue microarray. Isolated human islets, human pancreatic beta and ductal cell lines were also studied. Immunological and molecular approaches were employed to examine the expression and cellular localisation of the known CAR isoforms in human pancreas. One specific isoform of CAR (CAR-SIV) with a unique C terminal PDZ binding domain, was highly expressed in human beta cells at the protein level. Surprisingly, it was distributed in a punctate manner mainly within the cytoplasm of the cells, rather than at the cell surface. In human beta cells, within the cytoplasm CAR-SIV co-localised with ZnT8, PC1/3 and insulin but less so with proinsulin suggesting that CAR-SIV is associated with insulin secretory granules. Immunogold labelling and electron microscopic analysis revealed that CAR-SIV is localised both to maturing insulin secretory granules and to fully mature, dense-core (insulin) secretory granules. Intriguingly, CAR-SIV colocalises and interacts with a cytosolic protein, PICK1, which plays a role in the budding, maturation and trafficking of insulin secretory granules. On this basis, a model is proposed whereby CAR-SIV and PICK1 interact to regulate the maturation and trafficking of insulin secretory granules. Overall, this study suggests that the specialised role and subcellular localisation of CAR-SIV in human beta cells may contribute to their sensitivity to enteroviral infection following externalisation of the protein at the cell surface, during insulin exocytosis.
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Lundberg, Alexander. "Studying the Oligomerization of the Kinase Domain of Ephrin type-B Receptor 2 Using Analytical Ultracentrifugation and Development of a Program for Analysis of Acquired Data." Thesis, Linköpings universitet, Kemi, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-110376.
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Ephrin type-B receptor 2 (EphB2) is a receptor tyrosine kinase which phosphorylates proteins and thereby regulates cell migration, vascular development, axon guidance synaptic plasticity, and formation of borders between tissues. It has been seen overexpressed in several cancers, which make it an interesting protein to study. In this thesis EphB2 kinase domain (KD) and juxtamembrane segment with kinase domain (JMS-KD) have been expressed, purified and studied using analytical ultracentrifugation to evaluate the oligomerisation of the KD and how the double mutation S677/680A affects this. A program for data analysis have been written and used for analysis of the acquired data. The values of the dissociation constant were 2.94±1.04 mM for KD wild type and 3.46±2.26 mM for JMS-KD wild type have been calculated. Due to varied problems with the measurements no data was acquired on the double mutant, and not enough data was gained to draw any conclusions. Additional experiments will be needed to understand the oligomerisation of this intriguing protein.
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Zhang, Xiaoming. "Etude du rôle des IFN de type I et des cellules B productrices d'IL-10 dans le contrôle de l'inflammation néonatale médiée par les TLR." Paris 6, 2007. http://www.theses.fr/2007PA066274.
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La période néonatale est caractérisée par une forte sensibilité aux maladies infectieuses ainsi que de faibles réponses immunitaires. Nous avons donc étudié la contribution d’un deficit de la réponse immunitaire innée dans ces phénomènes, en analysant la réponse inflammatoire innée à des agonistes des TLR. Dans un premier temps, nous avons mis en evidence un deficit de la réponse inflammatoire à des ligands de TLR chez la souris nouveau-né, ceci comparé à l’adulte. Toutefois, in vitro les cDC, les pDC et les cellules myéloides CD11b+ provenant du nouveau-né sont pleinement fonctionnelles dans leur capacité à produire des cytokines pro-inflammatoires. En revanche, in vivo l’aministarytion de ligand de TLR conduit à une forte production d’IL-10 par cellules B CD5+. En labsence des cellules B CD5+ ou du gene de l’IL-10, on observe une augmentation des réponses inflammatoires néonatales qui peuvent s’avérer létales. Le transfer de cellules B CD5+ compétentes pour la production d’IL-10 permet de protéger ces souris. Nous avons ensuite étudié le rôle des IFNs de type I dans la réponse inflammatoire néonatale. Si chez la souris adulte, les IFNs de type I ont un role positif sur le dévellopement de la réponbse inflammatoire induite par des ligands de TLR, en revanche chez le nouveau-né ils contribuent à contrôler la réponse inflammatoire en augmentant la capacité des cellules B CD5+ à produire de l’IL-10. Ainsi, le transfer de cellules B néonatales déficientes pour le recepteur aux IFNs de type I ne permet de protéger contrziement à des cellules B de phénotype sauvage. L’ensemble de ces résultats a permis de mettre en évidence un mécanisme de contrôle de la réponse inflammatoire induite par l’activation de la voie TLR, par la mobilisation des cellules B CD5+ productrices d’IL-10 coordonnée à l’action des IFNs de type I. Le nombre élevé de celllules B CD5+ au cours de la période néonatale comparé à l’adulte suggère que ce processus est controlé au niveau du développement. Si ce mécanisme de régulation de la réponse inflammatoire au niveau systémique peut être considéré comme un moyen de maintenir un environnement sans danger dans des conditions d’induction de l’inflammation, il pourrait aussi contribuer à la forte sensibilité des nouveau-nés aux infections
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Олешко, Тетяна Богданівна, Татьяна Богдановна Олешко, and Tetiana Bohdanivna Oleshko. "Зв’язок поліморфізму генів ендотеліну та ендотелінового рецептора з механізмами основних проявів ішемічного інсульту." Thesis, Сумський державний університет, 2017. http://essuir.sumdu.edu.ua/handle/123456789/65432.
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Дисертація присвячена вивченню впливу Lys198Asn- і C+70G- поліморфних варіантів генів EDN1 та EDNRA на розвиток ішемічного атеротромботичного інсульту (ІАТІ). Однонуклеотидний поліморфізм гена
EDN1 є самостійним незалежним фактором ризику ІАТІ. У осіб, що є гомозиготами за мінорним алелем, ризик розвитку ІАТІ більший у 4 рази, ніж у гомозигот за основним алелем (Р = 0,007; OR = 4,046). Зазначений ризик зростає в осіб чоловічої статі, пацієнтів із надмірною масою тіла, артеріальною
гіпертензією та без звички курити. Урахування поправки на інші коваріанти, що характеризують дані про стать, вік, ІМТ пацієнтів, наявність або відсутність у них АГ та звички курити дозволило виявити збільшення ймовірності настання ІАТІ у носіїв Asn/Asn-генотипу у 8,1 раза (Рпопр = 0,001; ORпопр = 8,059), порівняно з гомозиготами за основним алелем. Щодо поліморфного локусу C+70G гена EDNRA, то статистично значущого зв'язку його генотипів із розвитком ішемічного інсульту не виявлено.
Аналіз поєднаного впливу засвідчив, що співпадіння гомозиготи за мінорним алелем за Lys198Asn-поліморфізмом та одного із трьох можливих генотипів за C+70G-сайтом асоціюється із високим ризиком розвитку ІАТІ. При цьому збіг гетерозигот за двома сайтами також призводить до значного збільшення ризику розвитку ішемічного інсульту. Також виявлено, що поєднання в однієї особи артеріальної гіпертензії з носійством Asn-алеля за поліморфізмом гена EDN1 пов’язане з високим ризиком настання ІАТІ.Диссертация посвящена изучению влияния Lys198Asn- и C+70G-полиморфных вариантов генов EDN1 и EDNRA на развитие ишемического атеротромботического инсульта (ИАТИ). Однонуклеотидный полиморфизм гена EDN1 является самостоятельным независимым фактором риска ИАТИ. У лиц, являющихся гомозиготами по минорному аллелю, риск развития ИАТИ больше в 4 раза, чем у гомозигот по основному аллелю (Р = 0,007; OR = 4,046). Указанный риск возрастает у лиц мужского пола, пациентов с избыточной массой тела, артериальной гипертензией и без привычки курить. Учет поправки на другие коварианты, характеризующие данные о поле, возрасте, ИМТ пациентов, наличие или отсутствие в них АГ и привычки курить, позволил выявить увеличение вероятности развития ИАТИ у носителей Asn/Asn-генотипа у 8,1 раза (Рпопр = 0,001; ORпопр = 8,059) по сравнению с гомозиготами по основному аллелю. Относительно полиморфного локуса C+70G гена EDNRA, то статистически значимой связи его генотипов с развитием ишемического инсульта не обнаружено. Анализ сочетанного воздействия показал, что совпадение гомозигот по минорному аллелю Lys198Asn-полиморфизма и одного из трех возможных генотипов по C+70G-сайту ассоциируется с высоким риском развития ИАТИ. При этом совпадение гетерозигот по двум сайтам также приводит к значительному увеличению риска развития ишемического инсульта. Также выявлено, что сочетание у одного человека артериальной гипертензии с носительством Asn-аллеля по полиморфизму гена EDN1 связано с высоким риском развития ИАТИ.
Thesis is dedicated to the study of the effect of Lys198Asn- and C+70G- polymorphic variants of EDN1 and EDNRA genes impact on the development of ischemic atherothrombotic stroke (IAS). The study group included 170 unrelated Ukrainian patients with a mean age of 64.7 ± 0.73 years who had IAS. The control group consisted of 124 individuals with the absence of cardio-vascular pathologies. Genotyping of EDN1 (Lys198Asn (rs5370)) and EDNRA (C+70G (rs5335)) gene polymorphisms was performed using PCR-RFLP (polymerase chain reaction with following restriction fragment length polymorphism analysis) method. Most statistical analyses were performed using Statistical Package for Social Science software (SPSS, version 17.0, Chicago, IL, USA). Multifactorial dimensionality reduction was used for modelling the interactions between loci. All statistical tests were two-sided, P < 0.05 was considered significant. The single nucleotide polymorphism of the EDN1 gene is an independent risk factor for the development of ischemic atherothrombotic stroke – in the homozygote for the minor allele, the probability of the onset of IAS is significantly higher than that of the homozygote for the main allele (ORcorrec = 8.059; Рcorrec = 0.001). The influence of the polymorphic site of the EDN1 gene on the development of ischemic atherothrombotic stroke has sexual characteristics. The risk of stroke is higher in women who are carriers of the minor Asn-allele than in the carriers of the main Lys-allele (OR = 2.800; P = 0.009), and in males – the homozygote in the minor allele compared to homozygotes in the main allele (OR = 3.534; Р = 0.034). It was found that the risk of IAS development is greater in the homozygote for the minor allele (Asn/Asn) with BMI ≥ 25 kg/m2 than in the homozygote for the main allele (OR = 4.583; P = 0.020); in heterozygote C/G with BMI < 25 kg/m2 than in C/C-genotype carriers (OR = 3.684; P = 0.049); in patients with arterial hypertension – carriers of the heterozygous Lys/Asn-genotype (OR = 1.951; P = 0.034) and homozygote in the minor allele (Asn/Asn) (OR = 4.107; P = 0.033) compared to homozygotes in the main allele; in the Asn/Asn carriers that do not smoke compared to Lys/Lys-genotype carriers (OR = 3.379; Р = 0.041). Dependence of IAS characteristics from Lys198Asn- and C+70G-polymorphic variants of EDN1 and EDNRA genes was established. For carriers of the Asn/Asn-genotype with BMI ˂ 25 kg/m2, simultaneous damage to the anterior, middle, posterior brain arteries and arteries of the vertebro-basilar basin is more frequent characteristic (P = 0.002). The association of the G/G-genotype with the predominant damage of vertebral and basilar arteries in persons with normal arterial pressure (P = 0.050) was revealed. The clinical course of moderate severity IAS is more frequent in the homozygote for the minor G/G-allele with BMI ≥ 25 kg/m2 (P = 0.020). In persons with arterial hypertension and non-smokers who are carriers of the Asn/Asn-genotype, IAS is more likely to be severe (P = 0.024 and P = 0.023 respectively). Analysis of the combined effect of polymorphic sites of endothelin route genes and other known risk factors for atherosclerosis on the IAS development allowed to create a classification model including the polymorphic site of Lys198Asn of the EDN1 gene and arterial hypertension (prognostic significance 62% by MDR method, P = 0.043). The combination of hypertension and carriage of minor Asnallele in one person is a significant predictor of an increased risk of ischemic atherothrombotic stroke.
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Haga, Christopher L. "Analysis of the role of FCRL5 and FIGLERs in B cell development, signaling and malignancy." Thesis, Birmingham, Ala. : University of Alabama at Birmingham, 2008. https://www.mhsl.uab.edu/dt/2008d/haga.pdf.
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Terry, Jennifer L. "The characterization of TRUSS : a novel scaffolding protein in tumor necrosis factor-[alpha] receptor-1 signaling /." Connect to full text via ProQuest. IP filtered, 2005.
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Thesis (Ph.D. in Immunology) -- University of Colorado, 2005.Typescript. Includes bibliographical references (leaves 190-212). Free to UCDHSC affiliates. Online version available via ProQuest Digital Dissertations;
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Vasques, Gabriela de Andrade. "Mutações em heterozigose no gene do receptor tipo B dos peptídeos natriuréticos (NPR2) são causa de baixa estatura inicialmente classificada como idiopática." Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/5/5135/tde-04022016-102040/.
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Nos últimos anos, o sistema do peptídeo natriurético do tipo C (CNP) e seu receptor (NPR-B) foi apontado como um importante regulador do processo de ossificação endocondral. Vários estudos em animais evidenciam o seu papel de estímulo à proliferação e diferenciação de condrócitos e secreção de matriz extracelular. Mutações bialélicas com perda de função do gene do NPR-B (NPR2) levam a uma doença denominada displasia acromesomélica do tipo Maroteaux (AMDM), uma displasia esquelética caracterizada por baixa estatura extrema. Observa-se que familiares de pacientes com AMDM carreadores de mutação no NPR2 têm estatura abaixo da média da população a qual pertencem, sugerindo um papel de mutações em heterozigose do NPR2 como causadoras de baixa estatura idiopática (BEI). Os objetivos deste estudo foram avaliar a presença de mutações no gene NPR2 em um grupo de pacientes com BEI e correlacionar os achados moleculares com o fenótipo dos pacientes e familiares. A região codificadora do gene NPR2 foi sequenciada pelo método de Sanger em 60 pacientes com diagnóstico de BEI. Foram identificadas cinco diferentes variantes alélicas missense em heterozigose no NPR2, cada uma em um único paciente. Essas variantes foram submetidas à análise funcional in vitro para avaliação da atividade da guanililciclase e microscopia confocal para localização intracelular dos receptores NPR-B. As variantes c.226T > C / p.Ser76Pro, c.788G > C / p.Arg263Pro e c.2455C > T / p.Arg819Cys segregam com o fenótipo de baixa estatura dentro das famílias e determinam um prejuízo funcional ao NPR-B. As três variantes geram proteínas que exercem efeito dominante negativo e os receptores NPR-B com as mutações p.Ser76Pro e p.Arg263Pro não se localizam na membrana celular. As variantes c.491C > G / p.Ala164Gly e c.1636A > T / p.Asn546Tyr não segregam com o fenótipo de baixa estatura nas famílias e não se evidenciou um efeito dominante negativo. O escore-Z da altura dos indivíduos carreadores das variantes funcionalmente deletérias variou de -4,5 a -1,7. Um dos pacientes e dois familiares apresentam desproporção corporal e um paciente tem metacarpos curtos. Como conclusão, mutações em heterozigose no gene NPR2 são causa de baixa estatura em 3 de 60 pacientes com diagnóstico inicial de BEI (5% da nossa casuística). Os indivíduos afetados têm graus variados de baixa estatura, sem um fenótipo característicoOver the past several years, C-type natriuretic peptide (CNP) and its receptor (NPR-B) system has emerged as an important regulator of endochondral bone growth. Animal models showed a CNP/NPR-B role in promoting chondrocyte proliferation and differentiation and matrix synthesis. Biallelic loss-of-function mutations in NPR-B gene (NPR2) cause acromesomelic dysplasia type Maroteux (AMDM), a skeletal dysplasia with extreme short stature. Relatives of patients with AMDM, heterozygous for NPR2 mutations, were noted to be shorter than expected for their population of origin, suggesting that heterozygous mutations in NPR2 could be a cause of idiopathic short stature (ISS). The objective of this study was to investigate the presence of NPR2 mutations in a group of patients with ISS and to correlate molecular findings with phenotype. The NPR2 coding region was sequenced by Sanger\'s method in 60 patients with ISS. Five different heterozygous missense variants in NPR2 were identified in five patients. The functional consequences of those variants were established using in vitro cell-based assay to determine guanylate cyclase activity and confocal microscopy to determine intracellular localization of NPR-B. The variants c.226T > C / p.Ser76Pro, c.788G > C / p.Arg263Pro and c.2455C > T / p.Arg819Cys segregated with short stature phenotype and were functionally deleterious. NPR-B receptors with these three variants have a dominantnegative effect and p.Ser76Pro and p.Arg263Pro NPR-B were not localized in the cell membrane. Cosegregation analysis of the variants c.491C > G / p.Ala164Gly and c.1636A > T / p.Asn546Tyr was inconclusive and they did not have a dominant negative effect. Carriers of functionally deleterious variants have a height SD score that ranged from -4.5 to -1.7. One of these patients and two relatives have disproportionate short stature and one has shortened metacarpal. In conclusion, heterozygous mutations in NPR2 gene are cause of short stature in 3 of 60 patients initially classified as ISS (5% of our cohort). Affected individuals have variable degrees of short stature without a distinct phenotype
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Traughber, Cynthia Alicia. "The Opposing Effects of HDL Metabolism on Prostate Cancer." Case Western Reserve University School of Graduate Studies / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=case1590670749249322.
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Maureira, Álvaro Danilo Cerda. "Receptor scavenger BI: efeito de polimorfismos e atorvastatina na expressão gênica em indivíduos hipercolesterolêmicos." Universidade de São Paulo, 2009. http://www.teses.usp.br/teses/disponiveis/9/9136/tde-06122011-115728/.
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O receptor scavenger classe B tipo I (SR-BI) media a captação seletiva do colesterol da lipoproteina de alta densidade (HDL) e participa no effluxo do colesterol livre para aceptores lipoprotéicos. A HDL tem um importante rol aterogênico associado com sua participação no transporte reverso do colesterol. Polimorfismos no gene que codifica para o SR-BI (SCARB1) foram relacionados com alterações do perfil lipídico sérico e outros fatores de risco associados com doença cardiovascular. As estatinas são inibidores da síntese do colesterol utilizados no tratamento da dislipidemia. Vários polimorfismos em genes envolvidos no metabolismo intermediario de lipideos foram relacionados com diferenças na resposta a hipolipemiantes. Com a finalidade de avaliar o efeito de polimorfismos do SCARB1 sobre o perfil lipídico sérico, expressão gênica e a resposta a estatinas, foram selecionados 185 indivíduos normolipidêmicos (NL) e 147 pacientes hipercolesterolêmicos (HC). Os pacientes HC foram tratados com atorvastatina (10 mg/dia/4 semanas). DNA e RNA foram extraídos de amostras de sangue periférico. Os polimorfismos de nucleotídeo único (SNP) G4A, In5C>T e Ex8C>T foram detectados por PCR-RFLP. A expressão de RNAm do SCARB1 em células mononucleares de sangue periférico (CMSP) foi analisada por PCR em tempo real usando o gene da Ubiquitina c (UBC) como referência endógena. Nos indivíduos HC, as freqüências dos alelos raros G4A (12%), In5C>T (7%) e Ex8C>T (40%), no grupo HC, foram similares às encontradas no grupo NL (4A: 15%, In5T: 7%, e Ex8T: 35%, p>0,05). O alelo SCARB1 4A (genótipos GA + AA) foi associado com valores diminuídos de apoAI no grupo NL. O alelo In5T foi associado com maior concentração LDL-C sérico (p=0,029), em NL, e com apoB e razão apoB/apoAI elevadas (p>0,05) no grupo HC. O SNP SCARB1 Ex8C>T não foi relacionado com o perfil lipídico sérico basal, embora os portadores do genótipo Ex8CC foram associados com resposta reduzida ao tratamento com atorvastatina mostrando menor variação de colesterol total, LDL-C, apoB e razão apoB/apoAI. O SNP Ex8C>T foi associado com maior probabilidade (OR=3,1; 95% IC: 1,00-9,5; p=0,044) de ter uma resposta à atorvastatina diminuída. Os SNPs SCARB1 In5C>T e Ex8C>T estão em desequilíbrio de ligação. O haplótipo G1C5C8/G1T5C8 foi associado com concentrações basais elevadas de triglicérides e VLDL-C em NL e diminuídas de HDL-C e apoAI em HC. Os haplótipos G1C5C8/A1C5C8 e C5C8/C5C8 tiveram variação diminuída da apoB quando comparados com os outros haplótipos, G1C5C8/A1C5C8 e o diplótipo C5C8/C5C8 também apresentou uma variação reduzida da razão apoB/apoAI. Os SNPs G4A e In5C>T estão associados com diminuição da expressão gênica do SCARB1 em NL. O tratamento com atorvastatina não modifica a expressão de RNAm do SCARB1 em CMSP nos HC. Esses resultados são sugestivos de que os polimorfismos no SCARB1 estão associados com valores basais do perfil lipídico sérico e de expressão de RNAm do SCARB1, assim como de resposta à atorvastatina.The scavenger receptor class B type I (SR-BI) mediates the selective uptake of the high density lipoprotein (HDL) cholesterol and it participates in the free cholesterol efflux to lipoprotein acceptors. HDL has an important antiatherogenic role associated with important activity in the cholesterol reverse transport. Polymorphisms in the SR-BI gene (SCARB1) have been related to variations on plasma lipoprotein profile and other risk factors for cardiovascular disease. Statins are potent inhibitors of cholesterol synthesis prescribed for treatment of the dislipidemia. Several polymorphisms in genes involved in intermediary metabolism of lipids have been related to differences in response to lowering-cholesterol drugs. In order to evaluate the effect of SCARB1 polymorphisms on serum lipids, gene expression and lipid-lowering response to atorvastatin, 185 normolipidemic (NL) and 147 hypercholesterolemic (HC) individuals were selected. HC individuals were treated with atorvastatin (10 mg/day/4 weeks). DNA and RNA were extracted from peripheric blood mononuclear cells (PBMC). SCARB1 mRNA expression was analyzed by real time PCR using ubiquitin c gene (UBC) as endogenous reference. The frequencies of the rare alleles in HC group (G4A: 12%; In5C>T: 7%, and ExC>T: 39%) were similar to those found in NL individuals (4A: 15%, In5T: 7%, and Ex8T: 35%, p>0.05). The SCARB1 4A allele (GA+AA genotypes) was associated with lower apoAI concentration in NL. The In5T allele was associated with higher serum LDL-C (p=0,029) in NL individuals, and with higher apoB and apoB/apoAI ratio (p>0,05) in HC group. SCARB1 Ex8C>T SNP was not related to serum lipids profile, however Ex8CC genotype carriers had lower variation of total cholesterol, LDL-C, apoB and apoB/apoAI ratio in response to atorvastatin. SCARB1 Ex8C>T was associated with higher chance to have a lower atorvastatin response (OR=3.1, 95% CI: 1.00-9.5; p=0.044). SCARB1 In5C>T and ExC>T were in linkage disequilibrium. G1C5C8/G1T5C8 SCARB1 haplotype was associated with higher level of triglycerides and VLDL-C in NL and lower HDL-C and apoAI levels in HC individuals. G1C5C8/A1C5C8 haplotype and C5C8/C5C8 diplotype had lower variations on apoB than the other haplotypes, and G1C5C8/A1C5C8 had also lower variation on apoB/apoAI ratio. G4A and In5C>T SNPs are associated with lower SCARB1 mRNA expression in PBMC of NL individuals. Atorvastatin therapy did not modify the expression level of the SCARB1 transcript in HC. Our results suggest that SCARB1 polymorphisms are associated with basal serum lipids profile, mRNA SCARB1 expression and atorvastatin response.
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Moilanen, A. M. (Anne-Mari). "Identification of novel drug targets for the treatment of heart failure." Doctoral thesis, Oulun yliopisto, 2012. http://urn.fi/urn:isbn:9789514299131.
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Abstract Heart failure (HF) is a complex pathological state, involving simultaneous alterations in several signalling pathways and changes in gene programming. In HF, activation of the neurohumoral factors and renin-angiotensin-aldosterone (RAA) system occurs as a compensatory mechanism to combat the abnormal ventricular function. Developments in cardiac gene delivery methods have exerted a significant impact to treat HF and to discover the novel molecular mechanisms associated with HF and other cardiac diseases. This study demonstrated that adenovirus–mediated gene delivery of B-type natriuretic peptide (BNP) into the anterior wall of the left ventricle decreased myocardial fibrosis and increased capillary density. Post-infarction BNP improved systolic function associated with normalization of cardiac sarcoplasmic reticulum Ca2+-ATPase (SERCA) 2 expression and phospholamban phosphorylation at Thr17. On the other hand, (Pro)renin receptor ([P]RR) gene delivery resulted deleterious effects on cardiac function and (P)RR activation induced distinct angiotensin II (Ang II)-independent extracellular matrix remodelling and worsening of cardiac function. (P)RR gene delivery resulted in Ang II-independent activation of extracellular-signal regulated (ERK1/2) phosphorylation and increased myocardial fibrosis. In conclusion, the present study indicates that myocardial BNP gene delivery can achieve pleiotropic, context-dependent, favourable effects on cardiac function and that BNP can act locally as a mechanical load–activated regulator of angiogenesis and fibrosis. These results also implicate that (P)RR blockers may display additional cardiac effects in addition to its ability to evoke effective RAA system blockade. Overall, the findings of this study provide a better understanding of the molecular mechanisms involved in the biological actions of BNP and (P)RR, and identify BNP and (P)RR as potential novel drug targets for the treatment of HFTiivistelmä Neuroendokriinisellä aktivaatiolla, jonka seurauksena aiheutuu muun muassa verisuonten supistumista ja laajenemista sekä nesteen kertymistä elimistöön, on tärkeä merkitys sydämen vajaatoiminnan kehittymisessä. Neuroendokriininen aktivaatio kompensoi sydämen vajaatoiminnan seurauksena tapahtuvaa kammioiden poikkeavaa toimintaa. Yksi keskeisimmistä verisuonia supistavista tekijöistä on reniini-angiotensiini-aldosteroni (RAA) -järjestelmä, ja verisuonia laajentaviin tekijöihin kuuluvat muun muassa natriureettiset peptidit, kuten B-tyypin natriureettinen peptidi (BNP) ja A-tyypin natriureettinen peptidi. Geeninsiirtomenetelmillä on ollut merkittäviä vaikutuksia uusien hoitomenetelmien kehittämisessä, sydämen vajaatoiminnan syiden selvittämisessä ja uusien kohdegeenien tunnistamisessa sydämen vajaatoiminnan hoitoon. Väitöskirjan tutkimustulokset osoittivat, että suora adenovirusvälitteinen geeninsiirto rotan sydämen vasemman kammion etuseinään on toimiva menetelmä uusien kohdegeenien löytämiseksi sydämen vajaatoiminnan hoitoon. BNP:n geeninsiirto vähensi merkitsevästi fibroosin muodostumista ja lisäsi verisuonten uudismuodostumista sydämessä. Sydäninfarktin jälkeen BNP paransi sydämen systolista toimintaa, johon liittyi aktiivisen kalsiumpumpun, SERCA2:n ja fosfolambaani-proteiinin fosforylaation normalisoituminen. (Pro)reniini reseptorin ([P]RR) geeninsiirto aiheutti angiotensiini II:sta riippumatonta solunulkoisen matriksin uudelleenmuotoutumista ja sydämen toiminnan huonontumista sekä lisääntynyttä sydämen fibroosia. Väitöskirjatutkimus antaa uutta tietoa solunsisäisistä molekulaarisista mekanismeista sydänsoluissa. BNP geeninsiirto aiheutti sydämen tautitilasta riippuvia suotuisia tapahtumia, ja se toimi paikallisesti muun muassa fibroosia ehkäisevänä tekijänä. (P)RR geeninsiirtotulosten perusteella voidaan olettaa, että (P)RR:n salpaus saattaa olla uusi tehokas hoitokeino sydämen vajaatoiminnan hoitoon
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Provost, Alexandra. "Dégénérescences maculaires liées à l'âge et cholestérol : implication du récepteur des HDL SR-B1 ?" Paris 6, 2007. http://www.theses.fr/2007PA066251.
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Les DMLA (dégénérescences maculaires liées à l’âge) première cause de cécité après 50 ans dans les pays industrialisés sont un ensemble de maladies hétérogènes influencées par des facteurs environnementaux. Elles sont caractérisées par la présence de dépôts lipidiques (drusens) dans la membrane de Bruch. Nous avons montré une co-expression du récepteur aux HDL SR-BI et de l’enzyme clé de la stéroïdogénèse StAR dans la rétine de rat adulte. L’exploration du phénotype oculaire de la souris déficiente pour le gène SR-BI après 30 semaines de régime athérogène (cholestérol + cholate) a montré une accumulation de dépôts sous-rétiniens riches en lipides et en A2E, une dégénérescence des photorécepteurs, un électrorétinogramme altéré, une activation locale du système immunitaire ainsi qu’un transport anormal des vitamines A et E. Nous avons donc caractérisé un modèle connu d’atherosclérose susceptible de permettre une meilleure compréhension de la genèse des drusens et des DMLA
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Burén, Jonas. "Glucose and lipid metabolism in insulin resistance : an experimental study in fat cells." Doctoral thesis, Umeå universitet, Institutionen för folkhälsa och klinisk medicin, 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-26.
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Type 2 diabetes is usually caused by a combination of pancreatic β-cell failure and insulin resistance in target tissues like liver, muscle and fat. Insulin resistance is characterised by an impaired effect of insulin to reduce hepatic glucose production and to promote glucose uptake in peripheral tissues. The focus of this study was to further elucidate cellular mechanisms for insulin resistance that may be of relevance for type 2 diabetes in humans. We used rat and human adipocytes as an established model of insulin’s target cells. Glucocorticoids, e.g. cortisol, can induce insulin resistance in vivo. In the present study, pretreatment of rat adipocytes in vitro for 24 h with the cortisol analogue dexamethasone produced a downregulation of glucose uptake capacity as well as a marked depletion of cellular insulin receptor substrate 1 (IRS-1) and protein kinase B (PKB), two proteins suggested to play a critical role in the intracellular signal transduction pathway of insulin. The amount of phosphorylated PKB in response to acute insulin treatment was decreased in parallel to total PKB content. The basal rate of lipolysis was enhanced, but insulin’s antilipolytic effect was not consistently altered following dexamethasone pretreatment. Alterations in blood glucose as well as insulin levels may be of great importance for cellular as well as whole-body insulin resistance. High glucose (≥15 mM) for 24 h induced a decrease in glucose uptake capacity in rat adipocytes and IRS-1 content was reduced whereas IRS-2 was increased. Long-term pretreatment with a high insulin concentration downregulated insulin binding capacity and when combined with high glucose, it produced a pronounced reduction of cellular IRS-1 and 2 content together with insensitivity to insulin’s effect to activate PKB and a decrease in glucose uptake capacity. A common denominator for a decrease in glucose uptake capacity in our rat adipocyte studies seems to be a decrease in IRS-1 content. Adipocytes from type 2 diabetes patients are insulin-resistant, but in our work the insulin resistance could be reversed by incubation of the cells at a physiological glucose level for 24 h. Insulin resistance in fresh adipocytes from type 2 diabetes patients was associated with in vivo insulin resistance and glycemic level and with adipocyte cell size and waist-hip ratio (WHR). As a potential mechanism for postprandial dyslipidemia in type 2 diabetes, we examined the nutritional regulation of subcutaneous adipose tissue lipoprotein lipase (LPL) activity. It was upregulated by ~40-50 % after a standardised lipid-enriched meal and this was very similar in type 2 diabetes patients and control subjects, suggesting that the postprandial hypertriglyceridemia found in type 2 diabetes is not explained by an altered nutritional regulation of LPL in subcutaneous fat. In conclusion, the present work provides evidence for novel interactions between glucocorticoids and insulin in the regulation of glucose metabolism that may potentially contribute to the development of insulin resistance. High levels of glucose and insulin produce perturbations in the insulin signalling pathway that may be of relevance for human type 2 diabetes. Cellular insulin resistance may be secondary to the diabetic state in vivo, e.g. via glucotoxicity. This is supported by our finding that insulin resistance in adipocytes from type 2 diabetes patients can be reversed after incubation at a physiological glucose level. Key words: adipocyte, insulin resistance, type 2 diabetes, insulin signalling, glucose uptake, insulin, glucose, dexamethasone, insulin receptor substrate, protein kinase B, GLUT4, lipoprotein lipase.
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Vondráková, Kateřina. "Role endotelinových receptorů typu A a B v modelu fokální ischemie u mláďat laboratorního potkana." Master's thesis, 2014. http://www.nusl.cz/ntk/nusl-332182.
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Hypoxic-ischemic insult is a most common form of perinatal brain damage that threatens a newborn's life and can leads to permanent neurological sequelae. However, detailed aspects of the cerebral ischemia in the immature brain stay unanswered. We decide to use the model of focal cerebral ischemia induced by intrahippocampal endothelin-1 (ET-1) in 12-days-old rats. The knowledge about consequences of ET-1 induced ischemia and the role of endothelin receptors (ETA and ETB) in ischemia-induced consequences in immature brain are poor at present. Agonists and selective antagonists of the ETA and ETB receptors were used to determine the role of these receptors in the development of ischemia, changes in regional blood flow and tissue oxygenation, local changes of biochemical parameters and acute neuronal death. Our results indicates, that activation of the ETA receptors causes a strong decrease of the blood flow, induced related hypoxia and subsequent neuronal degeneration, whereas activation of ETB receptors has likely modulatory role. Moreover, ischemia causes increase of excitatory amino acids concentration, whereas inhibitory amino acid, except taurine, decreased after ischemia. These facts provides new insights in a case of perinatal ischemia. This thesis demonstrates the wide range of different effects of...
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Kapakos, Georgia. "Modulation of Endothelin-1 and Insulin-like Growth Factor Type 1-induced Signaling by Curcumin in A-10 Vascular Smooth Muscle Cells." Thèse, 2011. http://hdl.handle.net/1866/6223.
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Les maladies cardio-vasculaires (MCV), telles que l’hypertension et l’athérosclérose, s’accompagnent de modifications structurales et fonctionnelles au niveau vasculaire. Un fonctionnement aberrant de la migration, l’hypertrophie et la prolifération des cellules musculaires lisses vasculaires (CMLV) sont des évènements cellulaires à l’origine de ces changements. L’endothéline-1 (ET-1) contribue à la pathogénèse des anomalies vasculaires, notamment via l’activation des protéines MAPK et PI3-K/PKB, des composantes clés impliquées dans les voies prolifératives et de croissance cellulaires. Il a été suggéré que le stress oxydant jouerait un rôle intermédiaire dans les effets pathophysiologiques vasculaires de l’ET-1. En conséquence, une modulation de la signalisation induite par l’ET-1 peut servir comme éventuelle stratégie thérapeutique contre le développement des MCV. Il apparaît de nos jours un regain d’intérêt dans l’utilisation des agents phyto-chimiques pour traiter plusieurs maladies. La curcumine, constituant essentiel de l’épice curcuma, est dotée de plusieurs propriétés biologiques parmi lesquelles des propriétés anti-oxydantes, anti-prolifératrices et cardio-protectrices. Cependant, les mécanismes moléculaires de son effet cardio-protecteur demeurent obscurs. Dans cette optique, l’objectif de cette étude a été d’examiner l’efficacité de la curcumine à inhiber la signalisation induite par l’ET-1 dans les CMLV. La curcumine a inhibé la phosphorylation des protéines IGF-1R, PKB, c-Raf et ERK1/2, induite par l’ET-1 et l’IGF-1. De plus, la curcumine a inhibé l’expression du facteur de transcription Egr-1 induite par l’ET-1 et l’IGF-1, dans les CMLV. Ces résultats suggèrent que la capacité de la curcumine à atténuer ces voies de signalisation serait un mécanisme d’action potentiel de ses effets protecteurs au niveau cardiovasculaire.Cardiovascular diseases (CVDs), including hypertension and atherosclerosis, are associated with vascular functional and structural changes. Some of the cellular events underlying these processes include aberrant vascular smooth muscle cell (VSMC) proliferation, hypertrophy and migration. Endothelin-1 (ET-1) has been implicated in the pathogenesis of vascular abnormalities through the hyperactivation of key components of growth promoting and proliferative signaling pathways, including MAPKs and PI3-K/PKB. Vascular oxidative stress has also been suggested to play an intermediary role in mediating ET-1-induced pathophysiological effects. Interference with ET-1-induced signaling may therefore serve as a potential therapeutic strategy against the progression of cardiovascular disorders. There is presently a surge of interest in the use of plant-derived phytochemicals for the treatment of various diseases. Curcumin, the main constituent of the spice turmeric, exhibits multiple biological properties, amongst them, antioxidant, anti-proliferative and cardioprotective properties. However, the molecular mechanisms of its cardiovascular protective action remain obscure. Therefore, in the present studies, we investigated the effectiveness of curcumin to inhibit ET-1-induced signaling events in VSMC. Curcumin inhibited ET-1-induced as well as IGF-1-induced phosphorylation of IGF-1R, PKB, c-Raf and ERK1/2, in VSMC. Furthermore, curcumin inhibited the expression of transcription factor early growth response-1 (Egr-1) induced by ET-1 and IGF-1, in VSMC. In summary, these results demonstrate that curcumin is a potent inhibitor of ET-1 and IGF-1-induced mitogenic and proliferative signaling events in VSMC, suggesting that the ability of curcumin to attenuate these effects may contribute as potential mechanism for its cardiovascular protective response.
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Chiou, Yu-Ya, and 邱郁雅. "Endothelin-1 Regulates Glucose Transporter-1 and Type A Endothelin Receptor." Thesis, 2000. http://ndltd.ncl.edu.tw/handle/79783388587247171111.
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碩士國立陽明大學
生物化學研究所
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We first observed that ET-1 can induce ETAR mRNA expression dose- and time- dependently in 3T3-L1 adipocytes. We also investigated that ET-1 can augment GLUT1 mRNA expression time-dependently. To use varieties inhibitors to find out the signaling pathway of ET-1 increasing GLUT1 mRNA expression, Our datas shown that the effect of ET-1 was inhibited by CHX and PD98059, not by U73122 and staurosporine. We used antagonists BQ123 which is selective for ETAR, and BQ788 which is selective for ETBR to figure out what kind of endothelin receptor subtype is involved in ET-1 inducing GLUT1 mRNA expression. We demonstrated that ET-1 augments GLUT1 mRNA expression may via ETAR, because the effect can be blocked by BQ123. We also examined that ET-1 induced ETAR mRNA expression can be blocked by CHX, U73122, PD98059,amd staurosporine simultaneously.Similarly the effect of ET-1 augmenting ETAR mRNA expression was inhibited by BQ123,too. We also reported that insulin and 8-bromo-cAMP can increase ETAR mRNA and GLUT1 mRNA expression time-dependently. We also observed that the synergistic effect of ET-1 and 8-bromo-cAMP on GLUT1 mRNA expression in 3T3-L1 adipocyte. According to these results, we concluded that：a) ET-1, insulin, and 8-bromo-cAMP can augment ETAR mRNA and GLUT1 mRNA expression, respectively. b) ET-1 may via ETAR activate MAPK to increase GLUT1 mRNA expression. 審定證明書 授權書 誌 ………………………………..1 縮寫表……………………………2 中文摘要…………………………5 英文摘要…………………………6 背景介紹…………………………7 材料………………………………14 方法……………………………….18 結果……………………………….30 討論……………………………….38 圖表……………………………….42 參考文獻………………………….62
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Kaufman, Gabriel N. "Therapeutic potential of endothelin receptor type A and bradykinin receptor B1 dual antagonism in osteoarthritis treatment." Thèse, 2010. http://hdl.handle.net/1866/5526.
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Nous avons préalablement démontré que l'endothéline-1 (ET-1), un peptide vasoconstricteur de 21 acides aminés, joue un rôle central dans le métabolisme des tissus articulaires et a des fonctions cataboliques sur le cartilage articulaire dans l'ostéoarthrose, en liant son récepteur de type A (ETA). Suite à la relâche du nonapeptide vasodilatateur bradykinine (BK), et l'augmentation d'expression du récepteur B1 des kinines (BKB1), ces médiateurs engendrent un cycle d'inflammation, une destruction du cartilage, et une douleur articulaire. Lors de cette étude, l'efficacité thérapeutique des antagonistes spécifiques du ETA et/ou BKB1 dans un modèle animal d'ostéoarthrose a été testée. Notre hypothèse est que l'antagonisme va diminuer la progression de la pathologie et de la douleur articulaire.
L'ostéoarthrose a été induite chez des rats par rupture chirurgicale du ligament croisé antérieur. Les animaux ont été traités par injections intra articulaire hebdomadaires des antagonistes peptidiques spécifiques du ETA et/ou BKB1. La douleur articulaire a été évaluée par le test d'incapacitance statique durant les deux mois postopératoires ; la morphologie articulaire a été examinée post mortem par radiologie et histologie.
On constate que le traitement a diminué la douleur et a préservé la morphologie articulaire ; la double inhibition a été plus efficace que la simple inhibition. En conclusion, l'antagonisme double d'ETA et BKB1 améliore la douleur chronique et prévient la dégradation articulaire dans l'ostéoarthrose, ce qui suggère que ces récepteurs peuvent être des cibles thérapeutiques potentiels pour le traitement de cette pathologie.The author's laboratory has previously shown that endothelin-1 (ET-1), a 21-residue vasoconstrictive peptide, plays a central role in joint tissue metabolism, and has a catabolic function in matrix collagen degradation in osteoarthritis. These effects occur primarily through ligation of the endothelin-1 receptor A subtype (ETA). The subsequent release of the nonapeptide vasodilator bradykinin (BK) in the joint microenvironment, and up-regulation of bradykinin receptor B1 (BKB1) expression, engenders a vicious cycle of synovial membrane inflammation, articular cartilage destruction, and joint pain. In the present work, we describe a preclinical study of the efficacy of treatment of surgically induced osteoarthritis with ETA and/or BKB1 specific peptide antagonists. We hypothesize that antagonism will diminish osteoarthritis progress and articular pain. Osteoarthritis was surgically induced in rats by transection of the anterior cruciate ligament. Animals were subsequently treated with weekly intra-articular injections of specific peptide antagonists of ETA and BKB1. Hind limb pain was measured by the static weight bearing test for two months post-operatively. Post-mortem, knee joints were analyzed radiologically and histologically. Local antagonist treatment diminished overall limb pain, and accelerated postoperative recovery, after disease induction. Treatment also protected joint radiomorphology and histomorphology, with dual antagonism being slightly more protective. ETA and BKB1 dual antagonism improves chronic pain and prevents joint degradation in osteoarthritis. They therefore represent a novel therapeutic target: specific receptor dual antagonism may prove beneficial in disease management.
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Druckenbrod, Noah R. "Migration of enteric neural progenitors and the role of endothelin receptor-B signaling /." 2009. http://www.library.wisc.edu/databases/connect/dissertations.html.
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