Dissertations / Theses: 'PDGF'

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Folestad, Erika Bergsten. "Studies of the novel PDGFs, focusing on PDGF-D /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-770-7/.

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Willetts, Karen Eve. "PDGF A and PDGF RÎ± in mammalian development." Thesis, University of Oxford, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.318900.

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Hoflack, Bernard, Pierre Jurdic, Thilo Riedl, Anne Gallois, and Maria Arantzazu Sanchez-Fernandez. "Osteoclasts control osteoblast chemotaxis via PDGF-BB/PDGF receptor beta signaling." Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2015. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-184120.

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BACKGROUND: Bone remodeling relies on the tightly regulated interplay between bone forming osteoblasts and bone digesting osteoclasts. Several studies have now described the molecular mechanisms by which osteoblasts control osteoclastogenesis and bone degradation. It is currently unclear whether osteoclasts can influence bone rebuilding. METHODOLOGY/PRINCIPAL FINDINGS: Using in vitro cell systems, we show here that mature osteoclasts, but not their precursors, secrete chemotactic factors recognized by both mature osteoblasts and their precursors. Several growth factors whose expression is upregulated during osteoclastogenesis were identified by DNA microarrays as candidates mediating osteoblast chemotaxis. Our subsequent functional analyses demonstrate that mature osteoclasts, whose platelet-derived growth factor bb (PDGF-bb) expression is reduced by siRNAs, exhibit a reduced capability of attracting osteoblasts. Conversely, osteoblasts whose platelet-derived growth factor receptor beta (PDGFR-beta) expression is reduced by siRNAs exhibit a lower capability of responding to chemotactic factors secreted by osteoclasts. CONCLUSIONS/SIGNIFICANCE: We conclude that, in vitro mature osteoclasts control osteoblast chemotaxis via PDGF-bb/PDGFR-beta signaling. This may provide one key mechanism by which osteoclasts control bone formation in vivo.

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Hoflack, Bernard, Pierre Jurdic, Thilo Riedl, Anne Gallois, and Maria Arantzazu Sanchez-Fernandez. "Osteoclasts control osteoblast chemotaxis via PDGF-BB/PDGF receptor beta signaling." PLOS one, 2008. https://tud.qucosa.de/id/qucosa%3A28994.

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BACKGROUND: Bone remodeling relies on the tightly regulated interplay between bone forming osteoblasts and bone digesting osteoclasts. Several studies have now described the molecular mechanisms by which osteoblasts control osteoclastogenesis and bone degradation. It is currently unclear whether osteoclasts can influence bone rebuilding. METHODOLOGY/PRINCIPAL FINDINGS: Using in vitro cell systems, we show here that mature osteoclasts, but not their precursors, secrete chemotactic factors recognized by both mature osteoblasts and their precursors. Several growth factors whose expression is upregulated during osteoclastogenesis were identified by DNA microarrays as candidates mediating osteoblast chemotaxis. Our subsequent functional analyses demonstrate that mature osteoclasts, whose platelet-derived growth factor bb (PDGF-bb) expression is reduced by siRNAs, exhibit a reduced capability of attracting osteoblasts. Conversely, osteoblasts whose platelet-derived growth factor receptor beta (PDGFR-beta) expression is reduced by siRNAs exhibit a lower capability of responding to chemotactic factors secreted by osteoclasts. CONCLUSIONS/SIGNIFICANCE: We conclude that, in vitro mature osteoclasts control osteoblast chemotaxis via PDGF-bb/PDGFR-beta signaling. This may provide one key mechanism by which osteoclasts control bone formation in vivo.

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5

Pontén, Annica. "Biological activities of novel platelet-derived growth factors, PDGF-C and PDGF-D /." Stockholm, 2004. http://diss.kib.ki.se/2004/91-7140-013-3/.

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Kowarik, Markus. "Expression, Lokalisation und funktionelle Bedeutung von PDGF und PDGF-Rezeptoren in der Hypophyse und in Hypophysentumorzellen." Diss., lmu, 2007. http://nbn-resolving.de/urn:nbn:de:bvb:19-75767.

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7

Andræ, Johanna. "PDGF in cerebellar development and tumorigenesis." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2001. http://publications.uu.se/theses/91-554-4987-5/.

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8

Eger, Glenda. "Regulation and Function of MAP Kinases in PDGF Signaling." Doctoral thesis, Uppsala universitet, Ludwiginstitutet för cancerforskning, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-301057.

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Platelet-derived growth factor (PDGF) is a family of signaling molecules that stimulates cell growth, survival and migration. PDGF is recognized by specific transmembrane proteins, the PDGF receptors, which relay the signals to the cell activating the Mitogen-activated protein (MAP) kinases and other signaling pathways. Aberrant activation of these pathways is frequently detected in cancer. Hence, the study of these processes is essential for identifying potential drug targets or diagnostic markers. In paper I, we identified Receptor Subfamily 4 Group A Member 1 NR4A1 to be regulated by PDGF via MAP kinases, clarifying the role of Extracellular signal–regulated kinases (Erk) 1/2, Erk5 and Nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) in its regulation. NR4A1 was found to be important for the tumorigenic potential, measured as anchorage-independent growth, of glioblastoma cells. Since the cellular responses elicited by PDGF result from the balance between phosphorylation and dephosphorylation events, we investigated the role of the dual specificity phosphatases DUSP4/MKP-2 and DUSP6/MKP-3. In paper II, we describe the crucial role of Erk1/2 and p53 in the expression of DUSP4/MKP2. Moreover, we observed that DUSP4/MKP-2 downregulation decreases Erk5 activation and accelerates PDGFRβ internalization and downregulation resulting in a specific inhibition of Signal transducers and activators of transcription (Stat) 3, Src and protein kinase C (PKC), and partially of p38, Stat1/5 and Phoshoplipase Cγ (PLCγ). In paper III, we report that DUSP6/MKP-3 creates a negative cross-talk between Erk1/2 and Erk5 and an auto-inhibitory feedback loop on the PI3-kinase/Akt pathway. In paper IV, we identify a new regulative mechanism of the PDGF pathway. PDGF induces Erk5 expression and activation that modulates the PDGFRβ activity. After Erk5 downregulation, the receptor undergoes to a faster and stronger activation that results in a faster internalization and degradation. In conclusion, we present a mechanism through which the PDGF/MAP kinases support tumor growth, and elucidate different regulatory pathways involved in PDGF signaling.

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Etzel, Nadine. "Einfluss PDGF-Rezeptor-spezifischer Antikörper auf die Chemotaxis mesenchymaler Progenitorzellen und deren Expression von PDGF-Isoformen und -Rezeptoren." [S.l. : s.n.], 2006. http://nbn-resolving.de/urn:nbn:de:bsz:289-vts-56711.

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10

Ekman, Simon. "Specific signaling through heteromeric PDGF receptor complexes." Doctoral thesis, Uppsala University, Department of Cell and Molecular Biology, 2000. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-1067.

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Platelet-derived growth factor (PDGF) is a potent mitogen and chemoattractant for mesenchymal cells and exert its effect by binding to two structurally related receptor tyrosine kinases, denoted α- and β-receptors. PDGF binding induces dimerization of its receptors, both homo-and heterodimerization, leading to their autophosphorylation on tyrosine residues and binding of downstream signaling molecules. This thesis describes autophosphorylation and binding of signal transduction molecules to homo- and heterodimeric PDGF receptor complexes.

Heterodimeric PDGF receptor complexes have been found to mediate a stronger mitogenic response than homodimeric receptor complexes. It was found that Tyr771 in the PDGF β-receptor was significantly less phosphorylated in the heterodimeric β-receptor compared to the homodimeric receptor, and this correlated with reduced binding of GTPase activating protein (GAP) for Ras and decreased activation of the Ras/Mitogen activated protein kinase pathway.

The mechanism behind the lowered phosphorylation of Tyr771 in the heterodimeric PDGF β-receptor was investigated. It was found that the SH2 domain-containing tyrosine phosphatase SHP-2 was responsible, at least in part, for the dephosphorylation of Tyr771 in the heterodimeric β-receptor.

PDGF-induced autophosphorylation of tyrosine residues in the receptors has been proposed to occur in trans between the receptor molecules in the dimers. We demonstrated by phosphopeptide mapping that all major autophosphorylation sites can be phosphorylated in trans, both in the PDGF α- and β-receptors. Analyses of the abilities of heterodimeric receptor complexes of one kinase-active and one kinase-inactive receptor to mediate mitogenicity, chemotaxis and activation of mitogen activated protein kinase revealed that the signaling capacities were retained. This illustrates a functional co-operation between the two receptor molecules in the dimer, where one receptor provides a functional kinase and the other acts as a substrate and provides docking sites for downstream signaling molecules.

Elucidating the mechanisms behind the unique signaling properties of the heterodimeric PDGF receptor complex, two heterodimer-specific autophosphorylation sites, Tyr692 and Tyr970, were identified and found to interact with the low molecular weight protein tyrosine phosphatase (LMW-PTP). Mutation of Tyr692 or Tyr970 to phenylalanine residues did not affect PDGF-induced mitogenicity, but the Tyr692 to phenylalanine mutation reduced the chemotactic response mediated by the heterodimeric PDGF receptor complex. A mechanism for the lowered chemotactic response was found to involve an increased RasGAP binding and a decreased SHP-2 binding to the heterodimeric β-receptor.

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11

Nilsson, Ingrid. "Hypoxia, PDGF and VEGF in Vascular Development." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-6894.

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12

Enarsson, Mia. "Roles of PDGF for Neural Stem Cells." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-4245.

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Bahm, Isabel. "PDGF signalling during Neural Crest Cell migration." Thesis, University College London (University of London), 2018. http://discovery.ucl.ac.uk/10041758/.

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Neural crest cells are a transient cell population, which migrates through the vertebrate embryonic body, and eventually gives rise to a many different cell types in the adult. Contact inhibition of locomotion (CIL) is a fundamental property of the collective migrating neural crest cells. CIL describes a process by which colliding cells change their direction upon collision and move away from each other, which has been linked to cell dispersion, boundary formation and metastasis. CIL is acquired in neural crest cells during Epithelial-to-Mesenchymal-Transition (EMT), by a switch in the expression of cadherins, from E to N-cadherin. To examine what governs this change I study PDGF signalling during Xenopus laevis cranial neural crest migration. Here I show that PDGFRα and its ligand PDGF-A are expressed in pre-migratory and migrating cranial neural crest cells. Inhibition of PDGF-A/PDGFRα impairs neural crest migration in vivo and cell dispersion in vitro. I find that PDGFRα inhibition leads to a decrease of N-cadherin levels in neural crest cells. Further, I demonstrate that PDGFRα signalling controls N-cadherin dependent CIL. This cellular response is controlled by the PI3K/AKT signalling pathway as a downstream effector of the PDGFRα cellular response in cranial neural crest cells. This data lead me to propose a novel mechanism by which PDGF signalling as a tissue-autonomous regulator of EMT is regulating N-cadherin dependent CIL during cranial neural crest cell migration in Xenopus laevis.

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Gillnäs, Sara. "PDGF-C signaling is required for normal cerebellar development : An analysis of cerebellar malformations in PDGF-C impaired mice." Thesis, Uppsala universitet, Institutionen för biologisk grundutbildning, 2021. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-445240.

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Platelet-derived growth factor-C (PDGF-C) and its tyrosine kinase receptor PDGFRɑ have been shown to contribute to several key processes during central nervous system (CNS) development, including normal vascularization and formation of cerebral ventricles and basal membrane of the meninges. Due to redundancy between PDGF-C and PDGF-A, PDGF-C specific roles are sometimes masked and difficult to determine. Using the double mutant Pdgfc-/-;PdgfraGFP/+ mouse (Mus musculus) strain we were able to detect and examine a new, undescribed phenotype of PDGF-C impaired mice, namely cerebellar malformations. These mutant mice displayed an upwards rotation of the cerebellar vermis with a severe posterior vermis hypoplasia and an enlarged fourth ventricle, suggesting PDGF-C/PDGFRɑ signaling as a novel candidate to induce Dandy-Walker malformation (DWM). Due to suspected cerebellar vascular malformation a quantification of diameter, density and number of vessels were performed. A significant increase (P < 0.05) of the number and density of vascular bed in the cerebellar nuclei was detected, however the vessel diameter was not significantly different (P > 0.05) in Pdgfc-/-;PdgfraGFP/+ mice in comparison with the control. Through immunofluorescence staining we detected discontinuation of the ependyma in the acute angle of the ventricular zone adjacent to the rhombic lip, interfacing the fourth ventricle and cerebellar anlagen. We further noted ectopic expression of rhombic lip derived cells in the ventricular zone, suggesting a misguided migration due to ablation of PDGF-C. We conclude that PDGF-C is an essential player in normal cerebellar development.

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15

Zhang, Xiao-Qun. "Functional Studies on the PDGFR α gene promoter and effects of autocrine PDGF-A stimulation in vivo." Doctoral thesis, Uppsala universitet, Institutionen för genetik och patologi, 2001. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-1455.

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Platelet-derived growth factor receptor α (PDGFRα) plays an important role during embryogenesis. After implantation, the patterns of expression of Pdgfrα and its ligand Pdgf-A undergo an "autocrine-paracrine transition", in that Pdgf-A becomes expressed in the ectoderm and epithelia, while Pdgfrα is expressed in the adjacent mesenchymal tissue. In human tumors, such as malignant glioma, both PDGF and PDGFRα are overexpressed within the same tissue, indicating that an autocrine PDGF loop is generated in the tumors. This thesis is focused on the in vivo functionality of the PDGFRα gene (PDGFRA) promoter, arid on the effect of autocrine PDGF-A stimulation in transgenic n-iice during embryogenesis. To test the in vivo promoter function of a human PDGFRA 2.2 kb 5' flanking fragment, we generated transgenic mouse lines and found that the 2.2 kb fragment was able to promote lacZ reporter gene expression in most of the endogenous Pdgfra expressing tissues. Absence of expression and "ectopic" expression of the transgenic lacZ were also observed. To investigate the autocrine PDGF effect, we produced autocrine PDGF-As (A short-chain) transient transgenic embryos. These transgenic embryos carried a 6 kb mouse Pdgfra 5' flanking sequence linked to a human PDGF-As cDNA. The pattern of expression of the PDGF-As transgene mRNA was similar to that of lacZ. Some of the transgenic embryos exhibited severe abnormal phenotypes, such as midline fusion defects in the cephalic and craniofacial region and small body size, and these embryos die at mid-gestation stage. These findings indicate that a paracrine pattern of expression and the dosage of PDGF are important for sustaining normal embryo development, especially with regard to the middline fusion in craniofacial regions. The possible signaling pathways that may be involved in regulating Pdgfra activity were also studied by comparison of patterns of mRNA expression of Gli, Ptc, and Paxl with that of Pdgfra. The results pointed to the possibility that the Shh signaling pathway may be involved in the regulation of Pdgfra expression for example during early bone and foregut development. The specific regulatory mechanisms may vary for different tissues.

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Sjöblom, Tobias. "Paracrine and autocrine functions of PDGF in malignant disease." Doctoral thesis, Uppsala University, Ludwig Institute for Cancer Research, 2002. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-2678.

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Growth factors and their receptors are frequently activated by mutations in human cancer. Platelet-derived growth factor (PDGF)-B and its tyrosine kinase receptor, the PDGF β-receptor, have been implicated in autocrine transformation as well as paracrine stimulation of tumor growth. The availability of clinically useful antagonists motivates evaluation of PDGF inhibition in these diseases.

In chronic myelomonocytic leukemia with t(5;12), parts of the transcription factor TEL and the PDGF β-receptor are fused, generating a constitutively signaling protein. Oligomerization and unique phosphorylation pattern of TEL-PDGFβR was demonstrated, as well as the transforming activity of TEL-PDGFβR, which was sensitive to PDGF β-receptor kinase inhibition.

Dermatofibrosarcoma protuberans (DFSP) is characterized by a translocation involving the collagen Iα1 and PDGF B-chain genes. The COLIA1-PDGFB fusion protein was processed to mature PDGF-BB and transformed fibroblasts in culture. The PDGF antagonist STI571 inhibited growth of COLIA1-PDGFB transfected cells and primary DFSP cells in vitro and in vivo through induction of apoptosis.

Paracrine effects of PDGF-DD, a ligand for the PDGF β-receptor, were evaluated in a murine model of malignant melanoma. PDGF-DD production accelerated tumor growth and altered the vascular morphology in experimental melanomas.

A validated immunohistochemical procedure for PDGF β-receptor detection was established and applied to normal tissues and more than 280 tumor biopsies. Perivascular and stromal expression was detected in 90% and 50%, respectively, of human tumors.

Recently, non-transformed cells in the tumor microenvironment have emerged as targets in cancer therapy. Selective sensitization of tumor fibroblasts to paclitaxel by STI571 was evaluated in vitro and in a xenograft model. Whereas neither drug alone caused growth inhibition, combination of the two significantly reduced tumor growth, suggesting anti-stromal therapy as a possible treatment modality in solid tumors.

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Kumar, Hashethra. "Does PDGF-BB have a role in bone remodelling?" Thesis, St George's, University of London, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.546797.

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18

Qin, Yong. "Targeting the Promoter Regions of PDGF Ligand and Receptor." Diss., The University of Arizona, 2008. http://hdl.handle.net/10150/194387.

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Aberrant expression of Platelet-derived growth factor A (PDGF-A) and PDGF receptor-β (PDGFR-β) play critical roles in the angiogenesis and proliferation of several malignancies. In this dissertation I explore the transcriptional regulatory role of the Gquadruplex- forming regions in the promoters of human PDGF-A and PDGFR-β, and identify new targets for developing small molecules to modulate their expression in tumors. For PDGF-A promoter, our studies focus on two essential nuclease hypersensitive elements, NHE(PDGF-A) and 5´-end far upstream 5´-SHS. The structural aspects of the intramolecular G-quadruplexes formed in NHE(PDGF-A) and the ligands to stabilize these secondary DNA structures have been investigated by using singlestranded and duplex DNA of the NHE(PDGF-A). We demonstrate that the G-quadruplexinteractive compound, TMPyP4, can selectively inhibit the basal promoter activity of PDGF-A, suggesting that the NHE(PDGF-A) G-quadruplex acts as a repressor in PDGF-A transcription. We also found that the 5´-SHS G-rich strand oligomer can invade the NHE(PDGF-A) and form a unique three-stranded complex in supercoiled plasmids, which is facilitated by potassium ions and TMPyP4. Therefore, we propose a novel molecular mechanism for transcriptional silencing of the NHE(PDGF-A) by 5´-SHS in the PDGF-A promoter, in that the formation of G-quadruplex in the NHE(PDGF-A) provides a platform for the G-rich strand of 5´-SHS to invade and form a partial duplex DNA with the C-rich strand of the NHE(PDGF-A), resulting in displacement of hnRNP K and thus transcription silencing. Prior to the studies describe here, the promoter of human PDGFR-β had not been identified. Herein, we have cloned and characterized the first functional promoter of human PDGFR-β gene. A crucial highly GC-rich region (NHE(PDGFR-β)) in the human PDGFR-β promoter has been identified by its hypersensitivity to the S1 nuclease. Further studies demonstrate that stable G-quadruplex structures can form in the G-rich strand of NHE(PDGFR-β). The G-quadruplex-interactive molecule, telomestatin, can selectively stabilize G-quadruplexes formed in the human PDGFR-β promoter and inhibit its expression in Daoy cells. On the basis of these results, we propose that ligandmediated stabilization of the G-quadruplex structure in the proximal promoter region of human PDGF-A or PDGFR-β can be used to modulate the expression of these protooncogenes.

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Alabud, Arwa. "Proteasomens roll för ligand inducerad fragmentation av PDGF-β receptorn." Thesis, Uppsala universitet, Institutionen för farmaceutisk biovetenskap, 2021. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-455265.

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Bakgrund: Platelet derived growth factor receptorn (PDGF receptorn) är en receptor i kroppen som tillhör typ III av Recetor tyrosine kinas (RTK) familjen. PDGF-β receptorn är en typ av dessa receptorer som enligt en studie klyvs i två delar efter ligandbindning med PDGF-BB ligand: till en extracellulär del och en intracellulär del. Hypotesen är att den extracellulära delen går till lysosomen medan den intracellulära delen går till proteasomen efter klyvningen. Syfte: Att undersöka rollen för proteasomen i ligandinducerad fragmentation av PDGF-β receptorn och se om det finns ko-lokalisation mellan receptorns extracellulära del och proteasomen. Dessutom ska det undersökas hur eventuell ko-lokalisering av PDGF receptorns extracellulära fragment med proteasomet påverkas när proteasomerna i cellerna inhiberas. Metod: Bj-hTERT celler stimulerades med PDGF-BB ligand under fyra olika stimuleringstidspunkter (0, 30, 60 och 90 min) och med hjälp av immunofluorescens undersöktes det om det fanns ko-lokalisering mellan proteasomen och PDGF-β receptorns extracellulära del. I ett annat experiment inhiberades även proteasomens aktivitet med inhibitoren MG132 och ko-lokalisationen mättes och jämfördes med kontrollceller behandlat med DMSO för de fyra stimuleringstidspunkterna. Resultat: För det första ko-lokalisationsexperimentet visades ingen större ko-lokalisering mellan proteasomen och receptorns extracellulära del för alla fyra tidspunkter. För det andra ko-lokalisationsexperimentet visades ingen skillnad i ko-lokalisationen mellan proteasomen och receptorns extracellulära fragment för cellerna vars proteasomaktivitet inhiberats och kontrollcellerna. Det visade sig däremot att proteasomen spelade roll för internaliseringen av receptorns extracellulära del in i cellen.

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Kłosowska-Wardęga, Agnieszka. "Combination Therapies Targeting PDGF and VEGF Signaling Pathways in Solid Tumors." Doctoral thesis, Uppsala universitet, Ludwiginstitutet för cancerforskning, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-119827.

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Vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) are independently involved in several cancer-associated mechanisms including autocrine stimulation of cancer cells, stimulation of tumor angiogenesis and regulation of interstitial fluid pressure (IFP). The scope of this thesis was to investigate the combinatory effect of anti-VEGF and anti-PDGF treatment on tumor angiogenesis and tumor IFP. Angiogenesis is a process of formation of blood vessels. Based on the tumors dependency on the blood vessels to supply them with oxygen and nutrients, several anti-angiogenic therapies have been tried and shown to have beneficial anti-tumor effects. More recently, anti-angiogenic treatment appeared to transiently “normalize” disorganized tumor vasculature and therefore to improve the uptake of cytotoxic agents. In the first study, treatment was performed on two tumor models that differ only with regard to the degree of maturation of the vasculature, reflected by different number of pericytes that are the target for anti-PDGF treatment in these tumors. The aim was to study the role of pericyte coverage in protecting endothelial cells from anti-VEGF therapies. In the pericyte-rich tumor model the combination treatment gave a more efficient anti-angiogenic effect. Interestingly, it was only a subset of pericytes that was sensitive for the treatment. In the second paper, the effect of anti-VEGF and anti-PDGF treatment on tumor IFP was measured. IFP is elevated in most solid tumors, which is linked to poor prognosis and higher recurrence rate. Additionally, this serves as a problem in ant-cancer therapies since it makes the uptake of cytotoxic agents inefficient. PDGF is known to actively regulate the IFP by regulating the contractile activity of fibroblasts, while VEGF regulates IFP primarily by affecting vessel leakiness. In the current study, combination of anti-VEGF and anti-PDGF therapies was shown to have an additive effect. However, the timing of administration of inhibitors appeared to be crucial. It was only short, but not long term combination treatment that further reduced IFP as compared to monotherapies. Surprisingly, the additive effect on IFP did not translate into an increased efficiency of chemotherapy when comparing combination treatment with monotherapies. The last paper is a follow up of the first study, where it was shown that combination of anti-VEGF and anti-PDGF treatment affect the tumor vasculature. Here we investigated if the anti-angiogenic effect improves treatment efficiency of a cytotoxic agent. There was a significant effect of the combination of anti-VEGF and anti-PDGF on Taxol treatment efficiency in this Taxol resistant tumor model. However, the mechanism for the treatment effect and the relative contribution of the targeted vasculature in the outcome of the therapy remains to be determined, since tumor cells were also sensitized for Taxol in vitro. In summary, we have shown that targeting of PDGF and VEGF signaling pathways simultaneously affect both vasculature and IFP to a higher extent than monotherapies.

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Wang, Chun-Chao. "Systematic Analysis of Crosstalk in the PDGF Receptor Signal Transduction Network." NCSU, 2008. http://www.lib.ncsu.edu/theses/available/etd-08072008-162743/.

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Intracellular signal transduction is traditionally characterized in terms of pathways, comprised of serial activation processes. Although it is appreciated that canonical signaling pathways are simply dominant routes of regulation embedded in larger interaction networks, relatively little has been done to quantify pathway crosstalk in such networks. Through quantitative measurements that systematically canvas an array of stimulation and molecular perturbation conditions, together with computational modeling and analysis, we have elucidated crosstalk mechanisms in the platelet-derived growth factor (PDGF) receptor signaling network, in which phosphoinositide 3-kinase (PI3K) and Ras/extracellular signal-regulated kinase (Erk) pathways are prominently activated. We show that, while PI3K signaling is insulated from crosstalk, PI3K enhances Erk activation in multiple ways. Whereas simultaneously blocking Ras and PI3K abolishes PDGF-stimulated Erk phosphorylation, each pathway makes an independent contribution to Erk activation, and PI3K affects Ras activation as well. The magnitudes of these effects depend strongly on the stimulation conditions, subject to saturation effects in the respective pathways and negative feedback loops. Motivated by those dynamics, a kinetic model of the network was formulated and used to precisely quantify the relative contributions of PI3K-dependent and -independent modes of Ras/Erk activation.

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Vassilikioti, S. "Studies on antisense inhibition of PDGF #beta#-receptor expression in cultured cells." Thesis, University of Cambridge, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.319894.

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Shibuya, Hideyuki. "TNFα, PDGF and TGFβ synergistically induce synovial lining hyperplasia via inducible PI3Kδ." Kyoto University, 2015. http://hdl.handle.net/2433/199195.

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Karlsson, Susann. "T-Cell Protein Tyrosine Phosphatase, a Regulator of the PDGF Signaling Pathway." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-107674.

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Keilhack, Nikolas [Verfasser]. "PDGF-BB fördert die Redifferenzierung in vitro expandierter humaner Gelenkchondrozyten / Nikolas Keilhack." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2011. http://d-nb.info/1010798057/34.

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Aravapalli, Kiran. "The effect of triiodothyronine on the expression of PDGF-BB in fibroblasts." Thesis, Boston University, 2013. https://hdl.handle.net/2144/12046.

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Thesis (M.A.)--Boston University
The thyroid gland consists of two types of cells that develop from distinct tissues. The parafollicular C-cells are derived from neural crest tissue and produce calcitonin, while the follicular cells produce thyroid hormone and are derived from endodermal tissue; thyroid hormone is the focus of this study. In the follicular cells, iodide is eventually metabolized into T4 and T3, with T4 being the primary production. Deiodinase 2 processes T4 into T3 because T3 serves the greatest physiological function. Thyroid hormone is crucial in maintaining basal metabolic rate and has a major effect on many organs, so in order for the body to optimally operate, thyroid hormone must be produced and utilized in a proper manner. However, the role of thyroid hormone in wound healing has not been properly addressed. The main steps in wound healing involve migration, proliferation, remodeling, and angiogenesis. Fibroblasts play a key role in all of these steps and hence, were the cells of choice in this study. Platelet derived growth factor- BB is critical in wound healing because it is potent in causing both the proliferation and migration of fibroblasts. In this study, we dosed fibroblasts with different concentrations of thyroid hormone in an attempt to see if the expression of PDGF-BB increased in fibroblasts dosed with thyroid hormone. Fibroblasts were passed, dosed with T3, lysed, and western blots were run to see if the expression of PDGF-BB changed depending on the concentration of T3. Previous studies conducted on mice and guinea pigs showed that an application of topical thyroid hormone cream onto wounds resulted in quicker healing. The next step is to find the individual mechanisms and proteins that thyroid hormone affects, using western blots. The T3 concentrations utilized were 10-7 M and 10-8 M and a control was used that contained fibroblasts with no thyroid hormone. The western blot films clearly showed an increase in the expression of PDGF-BB with the 10-7 M and 10-8 M fibroblasts compared to the control group. Thus, thyroid hormone could affect the migration and proliferation steps of wound healing through the expression of PDGF-BB. Unfortunately, this expression did not appear to be dose-dependent since the samples with less thyroid hormone, 10-8 M, contained an equal or heavier band than the 10-7 M samples. Hence, more experiments need to be run with more concentrations in order to obtain statistically significant data.

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Higa, Thaís Tiemi. "Imunolocalização de supressores (FOXO3a e PTEN) e ativadores (Akt e phospho-Akt) da transição de folículos primordiais e primários em tecido ovariano humano." Universidade de São Paulo, 2017. http://www.teses.usp.br/teses/disponiveis/17/17145/tde-26042018-152648/.

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Mulheres com risco de falência ovariana prematura, assim como aquelas diagnosticadas com câncer que desejam preservar sua fertilidade, têm como opção a criopreservação do tecido ovariano. Esse tecido seria destinado, dependendo do caso, ao reimplante posterior ou para o cultivo in vitro de folículos ovarianos isolados do tecido criopreservado. Nesse contexto, os folículos primordiais são uma população importante tanto por serem mais resistentes ao processo de criopreservação, como por representarem cerca de 90% da população total folicular. Porém o uso destes folículos para procedimentos de Reprodução Assistida ainda é bastante limitado, pois os mecanismos responsáveis pelo seu processo de ativação ainda não são completamente conhecidos. A via de sinalização fosfatidilinositol 3- quinase (PI3K) foi recentemente identificada como determinante para o controle da ativação dos folículos primordiais. Portanto o objetivo deste estudo foi identificar e localizar os fatores componentes da via: supressores (FOXO3a e PTEN) e ativadores (Akt e Phospho-Akt). O que ofereceria uma valiosa ferramenta para elucidar os mecanismos envolvidos na ativação do pool de reserva folicular e permitiria o desenvolvimento de sistemas de cultivo folicular que atuassem diretamente nestes mecanismos. Sendo assim, foi realizado um estudo transversal com amostras de tecido ovariano humano, que foram submetidas à reação imunohistoquímica dos fatores previamente citados. Foram incluídas na casuística 40 pacientes, com idade média de 27,7 anos ± 7,26. Foi realizada uma análise comparativa da expressão dessas proteínas entre os folículos primordiais e primários. Foi encontrada diferença significativa para a proteína Akt, (p<0,05) em que os folículos primordiais (oócito e células da granulosa) manifestaram mais expressão da proteína Akt em comparação aos folículos primários. Também foi encontrada diferença significativa para a proteína phospho-Akt, porém apenas nas células da granulosa, em que houve maior expressão em folículos primordiais comparados aos primários. Enquanto ambos os estágios tiveram marcação negativa para o PTEN e FOXO3a na maioria dos folículos analisados. Sendo assim, neste estudo não foi possível identificar dentre as proteínas escolhidas uma que tivesse expressão claramente característica de uma ou de outra fase folicular, não sendo possível inferir que a atividade de qualquer uma das proteínas fosse estritamente ligada à ativação dos folículo primordiais.
Women at risk of premature ovarian failure, as well as those diagnosed with cancer who wish to preserve their fertility, have, as option, the ovarian tissue cryopreservation. This tissue would be destined, depending on the case, to posterior reimplantation, or for the in vitro culture of ovarian follicles isolated from the cryopreserved tissue. In this context, primordial follicles are an important population of cells. As they are more resistant to the cryopreservation process and they represent about 90% of the whole follicular population. However, the use of these follicles for Assisted Reproduction procedures is still quite limited, since the mechanisms responsible for its activation process are not fully understood. The phosphatidylinositol 3-kinase (PI3K) signaling pathway has recently been identified as determinant for the control of primordial follicle activation. Therefore, the aim of this study was to identify and localize the components of this pathway: suppressors (FOXO3a and PTEN) and activators (Akt and phospho-Akt). This would offer a valuable tool to elucidate the mechanisms involved in the activation of the follicular reserve pool and would allow the development of in vitro culture protocols that would act directly in these mechanisms. Thus, a cross-sectional study with samples of human ovarian tissue was performed. These samples were submitted to the immunohistochemical reaction of the previously mentioned factors. Forty patients were included in the study, with a mean age of 27.7 ± 7.26. A comparative analysis of the expression of these proteins was performed between primordial and primary follicles. A significant difference was found for the Akt protein (p<0.05) in which the primordial follicles (oocyte and granulosa cells) showed more Akt expression than primary follicles. Another significant difference was found for the phosphor-Akt protein, but only for the granulosa cells, where there was a greater expression in primordial follicles compared to the primary ones. While both stages were negatively stained for PTEN and FOXO3a in most of the follicles analyzed. Thus, in this study it was not possible to identify among the selected proteins one that had clearly characteristic expression of one or the other follicular phase, and it was not possible to infer that the activity of any of the proteins was strictly linked to the activation of the primordial follicles.

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Valdivia, Maria Alejandra Medina. "Efeitos do PDGF-BB na taxa de proliferação e na adesão de células derivadas da granulação óssea a fragmentos radiculares." Universidade de São Paulo, 2017. http://www.teses.usp.br/teses/disponiveis/25/25146/tde-11062018-185848/.

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O objetivo deste estudo foi investigar o papel do fator de crescimento derivado de plaquetas-BB (PDGF-BB) na concentração de 300ng/ml na taxa de proliferação e adesão de células derivadas da granulação óssea humana a fragmentos radiculares periodontalmente comprometidos. Na primeira etapa do estudo, foi estabelecida cultura primária de células da granulação óssea de dois pacientes adultos, sistemicamente saudáveis, não fumantes. Após a expansão celular, as células foram caracterizadas para determinação do fenótipo por meio de ensaios de viabilidade celular, MTT, ensaio de atividade de fosfatase alcalina, ensaio de mineralização e caracterização imunohistoquímica por meio de citometria de fluxo (segunda etapa). Na terceira etapa do estudo, os efeitos da adição de PDGF-BB recombinante humano na concentração de 300ng/ml na taxa de proliferação e adesão de células derivadas da granulação óssea a superfícies radiculares periodontalmente comprometidas foram investigados. A taxa de proliferação celular estimulada pelo PDGF-BB (grupo teste) ou pelo meio de cultura (grupo controle) foi investigada por meio de contagem de células viáveis nos frascos de cultura após 1, 3, 5 e 7 dias do cultivo celular. Foram obtidos 30 fragmentos dentários a partir de dentes extraídos por razões periodontais. Os fragmentos foram raspados com curetas Gracey e condicionados com solução em gel de EDTA a 24% durante 3 minutos, lavados com solução de soro fisiológico, secos e posicionados em placas de 24 poços. Foram incubadas sobre os fragmentos tratados 1x104 células GO por 24 horas, seguido por fixação e preparo para análise por microscopia eletrônica de varredura (MEV). O número de células aderidas sobre os fragmentos foi analisado nas fotomicrografias. O padrão de crescimento das células GO foi compatível com células ósseas, com modificação do padrão do crescimento com o aumento do número de passagens. Houve atividade de fosfatase alcalina em meio osteogênico e convencional, com pico máximo aos 7 dias e atividade de mineralização estimulada ou não por meio osteogênico, com pico máximo aos 21 dias. A análise por meio de citometria de fluxo demonstrou que as células GO não expressaram CD105 e CD166 na 14a passagem, indicando sua diferenciação celular avançada nesse período. A adição de rhPDGF-BB resultou em mudança na taxa de proliferação celular, observando-se pico máximo de crescimento aos 7 dias, com diferenças estatisticamente significantes (p < 0.005; ANOVA post hoc Tukey) em relação aos períodos de 1, 3 e 5 dias. O ensaio de MTT demonstrou maior viabilidade celular no período de 48 hs, comparativamente aos períodos de 24 e 72 horas, quando a densidade óptica celular diminuiu de forma significativa (p< 0.05; Friedmann pósteste Dunn). No ensaio de adesão celular, pode-se observar que a adição de rhPDGFBB aumentou significativamente o número de células aderidas aos fragmentos dentários (p< 0.05; teste t não pareado com correção Welch), com alteração da morfologia celular. Esses resultados sugerem que as células GO tem características compatíveis com linhagem de células osteoblásticas, de fenótipo mais diferenciado após a 12a passagem. A adição de rhPDGF-BB (300ng/ml) resulta em aumento da taxa de proliferação das células GO e do número de células aderidas a fragmentos radiculares, indicando que, nesta concentração, o fator de crescimento é citocompatível, favorecendo a proliferação e adesão celular.
The goal of this study was to investigate the effects of recombinant human platelet derived growth factor (rhPDGF-BB) at the concentration of 300ng/ml in the proliferation and adhesion of human bone granulation cells to periodontally diseased root fragments. At the first stage of the study, the granulation tissue existent in healing sockets (21 days after its creation) was collected from two systemically healthy nonsmoking adults to the establishment of primary culture. The in vitro properties of bone granulation (BG) cell lineage were characterized by cell viability, MTT, alkaline phosphatase activity and mineralization assays. The effects of culture medium (control) and rhPGDF-BB 300ng/ml (test) in the proliferation and adhesion of BG cells were investigated. The rate of BG cells proliferation was investigated by the number of viable cells present at 1, 3, 5 and 7 days after platting. Thirty root fragments were obtained from teeth extracted for periodontal reasons. Root fragments were scaled and root planed, conditioned with EDTA 24% for 3 minutes, rinsed in saline solution, air-dryed and positioned in 24-well plates. Each fragment was seeded with 104 BG cells, fixated after 24 hours and prepared for analysis in SEM. The number of cells adhered to the fragments was analysed in photomicrographies. BG cells growth pattern was compatible with osteogenic cell lineage, showing modification with the increasing number of cell passage. GO cells expressed alkaline phosphatase activity in conventional and osteogenic culture medium, with maximum peak at 7 days, as well as mineralization activity stimulated or not by osteogenic or non-osteogenic culture medium, with maximum peak at 21 days. The analysis by flow cytometer showed that BG cells have not expressed CD105 and CD106 at the 14th passage, indicating its advanced cell differentiation. The addition of rhPDGF-BB resulted in modification of proliferation rate, with maximum peak observed at 7 days, significantly different from 1-, 3- and 5-day periods (p< 0.005; ANOVA post hoc Tukey). MTT assay showed greater cell viability after 48 hours than after 24 and 72 hours, when optical density has significantly diminished (p< 0.05; Friedmann post hoc Dunn). At cell adhesion assay, it could be observed that the adhesion of rhPDGF-BB has significantly increased the number of cells adhered to root fragments (p< 0.05; unpaired t test with Welchs correction), and alterations in cell morphology. These results suggest that BG cells present in vitro characteristics compatible with osteoblastic cell lineages, with a more differentiated phenotype after the 12th passage. The addition of rhPDGF-BB (300 ng/ml) results in increase of the rate of BG cell proliferation and in the number of cells adhered to root fragments, indicating that, at this concentration, the growth factor is compatible with BG cells and favors cells proliferation and adhesion.

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Watts, Susan Margaret. "Inhibition of neointima formation using the human saphenous vein organ culture model." Thesis, University of Bristol, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.264064.

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Vaillant, Pierre. "La platelet-derived growth factor : son role dans la fibrose pulmonaire idiopathique." Nancy 1, 1989. http://www.theses.fr/1989NAN11118.

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Ma, Haisha. "Regulation of Platelet-Derived Growth Factor Receptor Signaling and its Targeting in Cancer Therapy." Doctoral thesis, Uppsala universitet, Ludwiginstitutet för cancerforskning, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-248172.

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Overactivity of platelet-derived growth factor receptor (PDGFR) is a frequent event in many types of solid tumors. Therefore, it is of great importance to uncover the mechanisms that regulate PDGF/PDGFR signalling, to develop efficient inhibitors targeting this pathway. The first step of downregulation of PDGFR activity upon ligand binding is internalization; thus we investigated how endocytosis pathways affect PDGFR signaling. We showed that in Ras-transformed fibroblasts, the internalization of PDGFR is shifted from the routine clathrin-dependent endocytosis to macropinocytosis, which results in enhanced PDGFR activity and subsequent downstream signalling, promoting anchorage-independent growth. We were also interested in how intracellular trafficking regulates signalling attenuation of PDGFR. We found that His-domain containing protein tyrosine phosphatase (HD-PTP) positively regulates phosphorylation level of the ubiquitin-ligases c-Cbl and Cbl-b; consistently, silencing of HD-PTP led to a decreased level of PDGFR ubiquitination (paper II). Consequently, internalized PDGFR could not be sorted properly and escaped degradation. This resulted in enhanced activation of phospholipase C γ (PLCγ) and changed kinetics of signal transducer and activator of transcription (STAT) 3 signalling, which further increased colony formation of HD-PTP silenced cells in soft agar, indicating a tumor suppressor role of HD-PTP. Activation of PDGFR leads to stimulation of downstream pathways. We identified Fer kinase as a critical signal transducer downstream of PDGFR in a proteomic screen. We showed that Fer kinase is essential for PDGF-induced STAT3 activation; as a result (paper III), Fer depletion severely blunted the ability of PDGFR signalling to promote anchorage-independent growth in soft agar and delayed tumor initiation in a mouse model. The crosstalk between host and tumor plays a critical role in tumor progression. At present most anti-cancer drugs are targeting tumor cells; we were interested in how targeting tumor host cells affects the efficacy of anti-tumor therapy. We found that selective PDGFRβ inhibition in host cells exerted tumor inhibitory effects on growth and vascularization of tumors with autocrine PDGF signaling, whereas tumors lacking such stimulation show only minor response on tumor growth (paper IV). Meanwhile, we demonstrated that PDGF/PDGFRβ signalling promotes expression of NG2, a marker for pericytes.

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Zheng, Wei. "The LAR protein tyrosine phosphatase enables PDGF β-receptor activation and signal transduction." Thesis, University of Birmingham, 2013. http://etheses.bham.ac.uk//id/eprint/4364/.

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Many cellular activities including cell survival, proliferation, migration and differentiation are controlled by growth factors and their corresponding tyrosine kinases receptor (RTKs). Growth factor receptor activation is strictly regulated by protein tyrosine phosphatases (PTPs). Here I investigated whether the receptor protein tyrosine phosphatase (RPTP) LAR, which is known to modify the activity of several RTKs, also regulates platelet derived growth factor (PDGF) receptor activity and signalling. Mouse embryonic fibroblasts (MEFs) expressing mutant LAR lacking its phosphatase domains (LARΔP) showed reduced phosphorylation of PDGFβ receptor (PDGFβR) compared with wild type (WT) cells. This was rescued by re-expression of WT LAR. The decreased phosphorylation of the PDGFβR was independent of ligand concentration and occurred on all tyrosine residues, suggesting that LAR is required for full PDGFβR kinase activation. The decreased kinase activity reduced the amplitude or duration of the different signalling pathways activated downstream of the PDGFβR, and resulted in reduced proliferation in response to PDGF-BB. These findings demonstrate, for the first time, that LAR activity is required for PDGF-induced fibroblast proliferation. The inhibition of PDGFβR kinase activity in LARΔP cells was exerted via increased basal activity of the tyrosine kinase c-Abl and its substrate protein kinase Cδ (PKCδ). Ligand-induced PDGFβR dimerization is defective in LARΔP cells, possibly due to the observed increase in the Nherf2 protein associating with the PDGFβR. In summary, I have identified LAR as a new regulator of PDGFβR activity, and propose a novel mechanism where PDGF-induced activation of c-Abl serves as a negative feedback loop to terminate the PDGFβR kinase activity. This may occur via PKCδ activation promoting the association of Nherf2 with PDGFβR, thereby reducing ligand-induced receptor dimerization and kinase activation. In this model, LAR promotes PDGFβR activity by inactivating c-Abl.

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Werth, Christel. "Von Tumorzellen beeinflusste Viabilität und Motilität stromaler Fibroblasten : Regulation durch PDGF und Akt, PKB /." Düsseldorf, 2007. http://opac.nebis.ch/cgi-bin/showAbstract.pl?sys=000253824.

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Ye, Jieyu, and 叶洁瑜. "The role of platelet-derived molecules: PDGF and serotonin in the regulation of megakaryopoiesis." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B47244446.

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Investigations on platelet-derived growth factor (PDGF) and serotonin (5-HT), molecules stored in platelet granules, imply their potential effects in regulating megakaryopoiesis, which also intimates the existence of an autocrine and/or paracrine loop constructed by megakaryocytes/platelets and their granular constituents. In addition, numerous reports indicate that melatonin, a derivative from serotonin effectively enhances platelet counts in patients with thrombocytopenia. However, their exact roles on human megakaryocytes and the underlying mechanisms remain unknown. Present studies showed that PDGF, like thrombopoietin (TPO), significantly promoted platelet recovery and the formation of bone marrow colony-forming unit-megakaryocyte (CFU-MK) in an irradiated-mouse model. An increased number of hematopoietic stem/progenitor cells and a reduction of apoptosis were found in the bone marrow aspirate. In the M-07e apoptotic model, PDGF had a similar anti-apoptotic effect as TPO on megakaryocytes. Our findings demonstrated that PDGF activated the PI3-k/Akt signaling pathway, while addition of imatinib mesylate reduced p-Akt expression. Our findings suggested that the PDGF-initiated radioprotective effect is likely to be mediated via PDGF receptors (PDGFRs) with subsequent activation of the PI3-k/Akt pathway. We also provide a possible explanation that blockade of PDGFR may reduce thrombopoiesis and play a role in imatinib mesylate-induced thrombocytopenia. We explored how serotonin regulated megakaryopoiesis and proplatelet formation. Our results indicated that serotonin (5-HT) significantly promoted CFU-MK formation and reduced apoptosis on megakaryocytes through phosphorylation of Akt. These effects were attenuated by addition of ketanserin, a 5-HT2 receptor inhibitor. In addition, serotonin was able to stimulate the F-actin reorganization in megakaryocytes through activating the p-Erk1/2 expression. Bone marrow mesenchymal stromal cells (MSCs) are important in regulating megakaryopoiesis through stimulating the release of thrombopoietic growth factor, such as TPO. Our studies suggested that when activated by serotonin, bone marrow MSCs were induced to release significant amount of TPO. Furthermore, thousands of membrane-derived microparticles (MPs) arose from MSCs and the TPO RNA/proteins contained within MPs were also considerably increased under serotonin treatment. In summary, our findings demonstrated an important role serotonin played on megakaryopoiesis. This effect was likely mediated via 5HT2 receptors with subsequent activation of Akt and Erk 1/2 phosphorylation, which led to survival of megakaryocytes and proplatelet formation. Serotonin also stimulated TPO released from MSCs in both dissociative and MP-encapsulated form, which indirectly promoted megakaryopoiesis. The effects of melatonin on megakaryopoiesis were also determined in our studies. Our findings showed that melatonin enhanced proliferation and reduced doxorubicin-induced toxicity on MKs. We further demonstrated the mechanism for melatonin-mediated protection on MKs maybe via repair of G2/M phase cell cycle arrest and inhibition of cell apoptosis on MK cells. The effects of melatonin on megakaryopoiesis were also determined in our studies. Our findings showed that melatonin enhanced proliferation and reduced doxorubicin-induced toxicity on MKs. We further demonstrated the mechanism for melatonin-mediated protection on MKs maybe via repair of G2/M phase cell cycle arrest and inhibition of cell apoptosis on MK cells.
published_or_final_version
Paediatrics and Adolescent Medicine
Doctoral
Doctor of Philosophy

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Basu, Souptik. "In vitro effects of VEGF and PDGF on cells involved in spinal cord injury." Thesis, Griffith University, 2022. http://hdl.handle.net/10072/414916.

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Spinal cord injury (SCI) is a debilitating disease affecting 13.1-220 cases per million people around the world. The pathogenesis of SCI is complex and is orchestrated by a plethora of cellular and biochemical reactions. The initial phase (primary) is a transient one which occurs as a result of the initial impact and other related vertebral fractures. Subsequently, leakage of blood spinal cord barrier and apoptosis of neurons with spread of axonal/myelin debris become the key reasons that trigger a flare of immunological secondary responses. The initial cells to get activated are the macrophages/microglia (tissue-resident macrophages). Once activated they set off a cascade of harmful/congenial reactions which may further promote or reduce inflammation, respectively. Only an imbalance to this equilibrium can predispose the local environment to a catastrophic outcome. Hence, targeting these cells in the acute phase of SCI is seen as an ideal strategy to reduce inflammation and promote early recovery. However, no definite drug therapy exists for SCI treatment, at present. New avenues are still being explored for consideration. One such strategy that has been introduced in the last few years is the use of growth factors, vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). Both are well known angiogenic promoters and have neuroprotective activity. Hence, when a combined administration was initiated on rat SCI models, it was seen as an ideal therapeutic approach. However, the outcomes were inconsistent and needs an empirical dissection of the contributions and interactions of different cellular and molecular modulators of SCI. This thesis has thus been focused on the study of (1) the effect of the growth factors on the cells involved in modulation of acute secondary stage of SCI (macrophages, microglia, astrocytes and neurons) and (2) on transplantable peripheral glial cells (Schwann Cells-SCs and olfactory ensheathing cells-OECs) and the corresponding interaction of the latter with host myeloid cells (macrophages), in vitro. I have used macrophages and administered single and combined VEGF and PDGF to understand how transcription regulator dynamics (Akt) is affected under non-inflammatory and inflammatory conditions. Subsequently, I have also targeted the activation of macrophages through nuclear factor kappa B (NF-κB) protein translocation assays and determined the expression of M1 (pro-inflammatory) and M2 (anti-inflammatory) genes. My results showed that Akt overactivation by combined factors led to a downregulation of the protein. Overactivation was evident as the growth factors triggered significant NF-κB translocation to nucleus in inflammatory state. Additionally, administration of PDGF in inflammation restricted Cd163 (M2 gene) downregulation, showing that growth factors promoted the prevalence of anti-inflammatory macrophages in inflammatory stage. When growth factors were administered on microglia, the tissue resident macrophage, only PDGF was able to activate microglia (based on shape morphology), but this did not stimulate significantly higher expression of A1-inducing genes (Tnfa, Il1a and C1q). In fact, PDGF also stimulated reactive astrocytosis in inflammation through microglia. Additionally, both PDGF and combined VEGF+PDGF treated microglia in inflammation triggered better synaptosomal regulation by astrocytes. Although, the growth factors did not promote A2 (anti-inflammatory) gene expressions, the combined VEGF+PDGF was able to promote neuroprotection by restriction of TAR binding protein-43 (TDP-43) translocation, a stress granule formed in neurodegeneration, into cytoplasm and downregulation of neuron specific enolase enzyme as evident on RT-qPCR assay. In the last phase of my thesis, I studied the role of the growth factors on the modulation of transplantable peripheral glial cells like SCs and OECs. The growth factors (single and combination) promoted higher proliferation of SCs as was evident through p75NTR and EdU proliferation assay. Although, inflammation reduced the rate of clearance of myelin debris, PDGF was able to stimulate it, in both non-inflammatory and non-inflammatory conditions. Additionally, PDGF also reduced the TNF-α secretion (a pro-inflammatory cytokine) by SCs in inflammation. I also assessed the role of the growth factors on nerve repair associated and myelin expressing genes in SCs. Inflammation downregulated nerve repair associated genes Jun and Sox2. While combined VEGF+PDGF reduced Gdnf compared to PDGF, there was no obvious change in inflammation. However, for myelin expression, PDGF significantly downregulated Pou3f1 gene, in normal and inflammatory conditions. Thus, PDGF favoured the production of nerve repair over myelination in acute inflammatory condition. In the final part of my thesis, I studied the interaction of macrophages with OECs when growth factors were administered in inflammatory condition. I also checked for temporal progression of the modulation of OEC functionality, having treated the macrophages for early (3 h), middle (24 h) and longer (48 h) time points. Combined VEGF+PDGF showed variable progression of NF-κB translocation at the early time point, where there was no difference from inflammatory mediator to the middle time point where it was significantly lower, and finally at the longer time point where it was higher but overall protein intensity was low for all the groups (VEGF, PDGF and VEGF+PDGF). An added advantage from combined VEGF+PDGF was that it did not produce excess pro-inflammatory cytokine (TNF-α and IL-6) over inflammatory condition and maintained the phagocytic abilities of OECs to clear myelin debris. Interestingly, macrophage conditioned media treated for longer time point with combined VEGF+PDGF in inflammation helped OECs to express nerve repair associated genes. In conclusion, this thesis provided an in vitro understanding of VEGF and PDGF (as single and combined dose) interaction with cells involved (host immune cells and transplantable peripheral glial cells) in SCI. Due to the presence of a hostile microenvironment associated with presence of variable cues, use of any individual growth factor to achieve positive therapeutic outcome would be difficult. Hence, a combination would help to ameliorate the approach and provide a congenial outcome. However, further interaction studies would be necessary to unravel other beneficial effects of the growth factors to promote is as a viable therapeutic strategy.
Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Pharmacy & Med Sci
Griffith Health
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Dietrich, Martin Frederik [Verfasser]. "Die Rolle von LRP1 in der Kontrolle des PDGF-Rezeptors in Osteoblasten / Martin Dietrich." Mainz : Universitätsbibliothek Mainz, 2011. http://d-nb.info/1016901798/34.

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Paré, Martin. "L’implication de SHP-1 en condition élevée de glucose inhibe la signalisation de l’insuline et du PDGF-BB dans les cellules musculaires lisses vasculaires hypoxiques." Mémoire, Université de Sherbrooke, 2016. http://hdl.handle.net/11143/9502.

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Résumé : Bien que l’hypoxie soit un puissant inducteur de l’angiogenèse, l’activation des facteurs de croissance est perturbée en hyperglycémie au niveau du pied et du cœur. Cette perturbation entraîne la perte de prolifération et de migration chez les cellules endothéliales, musculaires lisses vasculaires et péricytes empêchant la formation de nouveaux vaisseaux qui mènera à l’amputation des membres inférieurs chez les patients diabétiques. Une étude a démontré qu’une augmentation de la protéine tyrosine phosphatase Src homology-2 domain-containing phosphatase-1 (SHP-1) en condition hyperglycémique chez les péricytes entraînait l’inhibition de la signalisation du PDGF-BB, ce qui résultait en le développement d’une rétinopathie diabétique. Nous avons alors soulevé l’hypothèse que l’expression de SHP-1 dans les cellules musculaires lisses vasculaires affecte la prolifération et la migration cellulaire par l’inhibition de la signalisation de l’insuline et du PDGF-BB en condition diabétique. Nos expérimentations ont été effectuées principalement à l’aide d’une culture primaire de cellules musculaires lisses primaires provenant d’aortes bovines. Comparativement aux concentrations normales de glucose (NG : 5,6 mM), l’exposition à des concentrations élevées de glucose (HG : 25 mM) pendant 48 h a résulté en l’inhibition de la prolifération cellulaire par l’insuline et le PDGF-BB autant en normoxie (20% O2) qu’en hypoxie (24 dernières heures à 1% O2). Lors des essais de migration cellulaire, aucun effet de l’insuline n’a été observé alors que la migration par le PDGF-BB fut inhibée en HG autant en normoxie qu’en hypoxie. L’exposition en HG à mener à l’inhibition de la signalisation de la voie PI3K/Akt de l’insuline et du PDGF-BB en hypoxie. Aucune variation de l’expression de SHP-1 n’a été observée mais son activité phosphatase en hypoxie était fortement inhibée en NG contrairement en HG où on observait une augmentation de cette activité. Finalement, une association a été constatée entre SHP-1 et la sous-unité bêta du récepteur au PDGF. En conclusion, nous avons démontré que l’augmentation de l’activité phosphatase de SHP-1 en hypoxie cause l’inhibition des voies de l’insuline et du PDGF-BB réduisant les processus angiogéniques des cellules musculaires lisses vasculaires dans la maladie des artères périphériques.
Abstract : Even though hypoxia is a strong angiogenic inducer, pro-angiogenic factor signaling pathways in peripheral limb and heart are altered by hyperglycemia. This disruption leads to loss of endothelial cells, vascular smooth muscle cells and pericytes proliferation and migration preventing new blood vessel formation which results in amputation of lower extremities in diabetic patients. A study has shown that increase expression of the protein tyrosine phosphatase Src homology-2 domain-containing phosphatase-1 (SHP-1) in hyperglycemic condition in pericytes caused PDGF-BB signaling inhibition resulting in the development of diabetic retinopathy. Our hypothesis is that SHP-1 expression in vascular smooth muscle cells inhibits cell proliferation and migration induced by insulin and PDGF-BB in diabetic condition. Our experiments were performed using primary culture of vascular smooth muscle cells (SMC) from bovine aortas. As compared to normal glucose concentrations (NG:5,6 mM), high glucose level (HG: 25 mM) exposure for 48h inhibited SMC proliferation induced by insulin and PDGF-BB in both normoxia (20% O2) or hypoxia (1% O2 for the last 24h). During cell migration assays, no effect of insulin was observed while PDGF-BB action of SMC migration was reduced in HG in both normal and low oxygen concentrations. HG exposure lead to inhibition of insulin- and PDGF-BB-stimulated PI3K/Akt signaling pathway in hypoxia. No variation of SHP-1 expression was observed in HG condition. However, SHP-1 phosphatase activity was elevated in HG condition during hypoxia as compared to NG concentrations. Finally, our data showed an association between SHP-1 and the PDGF receptor beta subunit. In conclusion, our results demonstrated that the increase of SHP-1 phosphatase activity in hyperglycemia and hypoxia environment caused inhibition of insulin and PDGF-BB signaling pathways reducing angiogenic processes in vascular smooth muscle cells contributing to peripheral arterial disease in diabetes.

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Dogan, Berivan Suzan. "Der Einfluss von PDGF-Rezeptorinhibitoren auf die Gefässentwicklung, die Proliferation und die Apoptose bei embryonalen Stammzellen der Maus : die Rolle von PDGF-Rezeptorinhibitoren bei der Differenzierung von Perizyten während der Vaskulogenese und Angiogenese /." Köln, 2008. http://opac.nebis.ch/cgi-bin/showAbstract.pl?sys=000254264.

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39

Venalis, Paulius. "Antifibrozinių priemonių paieška preklinikiniuose sisteminės sklerozės modeliuose." Doctoral thesis, Lithuanian Academic Libraries Network (LABT), 2010. http://vddb.laba.lt/obj/LT-eLABa-0001:E.02~2010~D_20101001_150707-46435.

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Sisteminė sklerozė (SSc) – viena sunkiausių ir fatališkiausių autoimuninių sisteminių reumatinių ligų, o bazinių vaistų stygius, šiai ligai gydyti, itin didelis. Į onkologinę klinikinę praktiką įdiegtas tirozinkinazių inhibitorius – imatinibo mezilatas(IM). IM blokuoja TGF-β ir PDGF intraląstelinio signalo perdavimą ir taip sąlygoja fibrozės prevenciją SSc pelių modelyje. Mums buvo svarbu išsiaiškinti, ar imatinibas gali turėti įtakos ne tik prevencijai, bet ir susiformavusiai fibrozei. Be to TGF-β ir PDGF blokavimas angiogenezėje, galėtų riboti daug žadančio fibrozės inhibitoriaus IM naudojimą gydant SSc. Darbo tikslas: įvertinti imatinibo mezilato poveikį fibrozės procesui ir endoteliui sisteminės sklerozės eksperimentiniuose modeliuose ir ląstelių kultūrose. Darbo uždaviniai: įvertinti imatinibo efektyvumą neuždegiminiame SSc modelyje ir patikrinti imatinibo mezilato efektyvumą uždegiminiame suformuotos fibrozės modelyje; ištirti, ar terapinės imatinibo mezilato koncentracijos daro neigiamą poveikį gyvybinėms endotelio funkcijoms; įvertinti imatinibo mezilato poveikį angiogenezės etapams. Mūsų gauti duomenys rodo, kad: IM ne tik sustabdė bet ir paskatino jau egzistuojančios (bleomicino sukeltos) odos firbrozės regresiją; IM ryškiai sumažino poodžio ir odos storį, bei normalizavo miofibroblastų skaičių Tsk-1 pelėse; IM neturėjo poveikio endotelio ląstelių bazinėms funkcijoms; IM neturėjo neigiamo poveikio angiogenezės etapams.
Systemic sclerosis (SSc) – is one of the most complicated and fatal systemic diseases, and the lack of effective therapy is very evident. The tyrosine kinase inhibitor imatinib mesylate (IM) was shown to inhibit TGF-β and PDGF signaling pathways and prevent the development of dermal fibrosis upon challenge with bleomycin in murine model of SSc. The aim of therapy is not only to stop disease progression, but even induce regression of preexisting fibrosis. On other hand, blocking TGF-β and PDGF signaling in angiogenesis might worsen the vascular manifestations of SSc. We found important to evaluate effectiveness of IM for the treatment of pre-established tissue fibrosis and to exclude that the anti-fibrotic effects of IM are complicated by inhibitory effects on endothelial cell functions. Aim of the study: assess the effect of IM on the process of fibrosis and endothelium in experimental models of systemic sclerosis and cell cultures. Objectives of the study: assess the effectiveness of IM on murine models of established fibrosis; evaluate if IM has an effect on basal functions of endothelial cells; assess effect of IM on the process of angiogenesis. We have shown that IM exerts potent antifibrotic effects in two different models of SSc. Imatinib was effective for prevention of fibrosis and for treatment of established dermal fibrosis. We’ve demonstrated that IM does not inhibit major functions of endothelial cells. Thus, IM might not augment further the preexisting vascular... [to full text]

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40

Venalis, Paulius. "The performance of antifibrotic agents in preclinical models of systemic sclerosis." Doctoral thesis, Lithuanian Academic Libraries Network (LABT), 2010. http://vddb.laba.lt/obj/LT-eLABa-0001:E.02~2010~D_20101001_150819-57019.

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Systemic sclerosis (SSc) – is one of the most complicated and fatal systemic diseases, and the lack of effective therapy is very evident. The tyrosine kinase inhibitor imatinib mesylate (IM) was shown to inhibit TGF-β and PDGF signaling pathways and prevent the development of dermal fibrosis upon challenge with bleomycin in murine model of SSc. The aim of therapy is not only to stop disease progression, but even induce regression of preexisting fibrosis. On other hand, blocking TGF-β and PDGF signaling in angiogenesis might worsen the vascular manifestations of SSc. We found important to evaluate effectiveness of IM for the treatment of pre-established tissue fibrosis and to exclude that the anti-fibrotic effects of IM are complicated by inhibitory effects on endothelial cell functions. Aim of the study: assess the effect of IM on the process of fibrosis and endothelium in experimental models of systemic sclerosis and cell cultures. Objectives of the study: assess the effectiveness of IM on murine models of established fibrosis; evaluate if IM has an effect on basal functions of endothelial cells; assess effect of IM on the process of angiogenesis. We have shown that IM exerts potent antifibrotic effects in two different models of SSc. Imatinib was effective for prevention of fibrosis and for treatment of established dermal fibrosis. We’ve demonstrated that IM does not inhibit major functions of endothelial cells. Thus, IM might not augment further the preexisting vascular... [to full text]
Sisteminė sklerozė (SSc) – viena sunkiausių ir fatališkiausių autoimuninių sisteminių reumatinių ligų, o bazinių vaistų stygius, šiai ligai gydyti, itin didelis. Į onkologinę klinikinę praktiką įdiegtas tirozinkinazių inhibitorius – imatinibo mezilatas(IM). IM blokuoja TGF-β ir PDGF intraląstelinio signalo perdavimą ir taip sąlygoja fibrozės prevenciją SSc pelių modelyje. Mums buvo svarbu išsiaiškinti, ar imatinibas gali turėti įtakos ne tik prevencijai, bet ir susiformavusiai fibrozei. Be to TGF-β ir PDGF blokavimas angiogenezėje, galėtų riboti daug žadančio fibrozės inhibitoriaus IM naudojimą gydant SSc. Darbo tikslas: įvertinti imatinibo mezilato poveikį fibrozės procesui ir endoteliui sisteminės sklerozės eksperimentiniuose modeliuose ir ląstelių kultūrose. Darbo uždaviniai: įvertinti imatinibo efektyvumą neuždegiminiame SSc modelyje ir patikrinti imatinibo mezilato efektyvumą uždegiminiame suformuotos fibrozės modelyje; ištirti, ar terapinės imatinibo mezilato koncentracijos daro neigiamą poveikį gyvybinėms endotelio funkcijoms; įvertinti imatinibo mezilato poveikį angiogenezės etapams. Mūsų gauti duomenys rodo, kad: IM ne tik sustabdė bet ir paskatino jau egzistuojančios (bleomicino sukeltos) odos firbrozės regresiją; IM ryškiai sumažino poodžio ir odos storį, bei normalizavo miofibroblastų skaičių Tsk-1 pelėse; IM neturėjo poveikio endotelio ląstelių bazinėms funkcijoms; IM neturėjo neigiamo poveikio angiogenezės etapams.

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41

Kallin, Anders. "Modulation of PDGF Receptor Signaling via the Phosphatase SHP-2 and the Docking Protein Gab1." Doctoral thesis, Uppsala University, Ludwig Institute for Cancer Research, 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3748.

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Platelet-derived growth factors (PDGF), a family of potent mitogens and chemoattractants for cells of mesenchymal origin, elicit their biological effects through the binding of two related receptor tyrosine kinases, denoted α- and β-receptors. The binding of PDGF to the receptors causes receptor dimerization and autophosphorylation on tyrosine residues. Src homology 2 (SH2) domain-containing proteins then bind the phosphorylated receptors, mediating further propagation of the signal. This thesis describes how the interaction between the PDGF receptors and some of their downstream targets can modify the cellular response to PDGF.

The tyrosine phosphatase SHP-2 has been implicated in activation of the Ras/MAPK pathway downstream of several receptor tyrosine kinases. We found that SHP-2 binds to phosphorylated Y763 in the PDGF β-receptor, in addition to the already reported binding to Y1009. Cells expressing PDGF β-receptors with Y763 and Y1009 mutated to phenylalanine exhibited decreased Ras-GTP loading and reduced activation of Erk2 in response to PDGF. Whereas these cells did not show any change in the mitogenic response to PDGF, the PDGF-induced chemotaxis was significantly reduced in cells expressing mutant compared to wild-type receptor.

The phosphorylation of Y771 of the PDGF β-receptor had been shown to be significantly lower in the αβ-heterodimeric receptor compared to in the ββ-homodimer, causing reduced binding of RasGAP to the heterodimer and increased Ras/MAPK activation. We could demonstrate that the reduced phosphorylation of Y771 is due to dephosphorylation by tyrosine phosphatases, including SHP-2.

SHP-2 had been shown to associate with the docking protein Gab1 after growth factor stimulation. We showed that the adaptor protein Grb2 was required for PDGF mediated phosphorylation of Gab1, and that phosphorylated Gab1, Grb2 and SHP-2 create a complex upon PDGF stimulation. Using a cell system with an inducible Gab1 expression, we further demonstrated that Gab1 increased SHP-2 activity in response to PDGF, without affecting the interaction between SHP-2 and the b-receptor. Induction of Gab1 correlated with an increase in both PDGF-induced Erk and p38 MAPK activation, whereas Akt activation was unaffected. The latter finding was in line with our observation that PDGF had no effect on the interaction between Gab1 and p85 of PI3’-kinase. The increase in MAPK activity after Gab1 induction and PDGF treatment did not correlate with an increase in PDGF-induced mitogenicity; instead these cells displayed more pronounced actin reorganization in response to PDGF.

In conclusion, our data indicate that SHP-2 regulates the PDGF response both through direct dephosphorylation of the receptor and through its interaction with Gab1. PDGF stimulated activation of SHP-2 seems to be correlated not only with mitogenesis, but also with reorganization of the actin cytoskeleton and cell migration.

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Ndolumingo, Maxime [Verfasser]. "Inhibierung beta-PDGF-Rezeptor-vermittelter Signalwege durch Rotwein in glatten Gefäßmuskelzellen der Maus / Maxime Ndolumingo." Köln : Deutsche Zentralbibliothek für Medizin, 2013. http://d-nb.info/1037401980/34.

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Schloen, Kathrin [Verfasser], and J. [Akademischer Betreuer] Wehland. "Charakterisierung von PDGF-induziertem peripheren und dorsalen zirkulären Membran 'ruffling' / Kathrin Schloen ; Betreuer: J. Wehland." Braunschweig : Technische Universität Braunschweig, 2010. http://d-nb.info/1175827541/34.

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Porsch, Helena. "Importance of Hyaluronan-CD44 Signaling in Tumor Progression : Crosstalk with TGFβ and PDGF-BB Signaling." Doctoral thesis, Uppsala universitet, Science for Life Laboratory, SciLifeLab, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-198165.

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In order for solid tumors to metastasize, tumor cells must acquire the ability to invade the surrounding tissue and intravasate into blood- or lymph vessels, survive in the circulation and then extravasate at a distant site to form a new tumor. Overexpression of the glycosaminoglycan hyaluronan, and its adhesion receptor CD44, correlate with breast cancer progression. This thesis focuses on the role of hyaluronan in tumor invasion and metastasis. In paper I, we demonstrated that upregulation of the hyaluronan synthesizing enzyme hyaluronan synthase 2 (HAS2) was crucial for transforming growth factor β (TGFβ)-induced epithelial-mesenchymal transition (EMT) in mammary epithelial cells. In paper II, we further demonstrated that silencing of HAS2 decreased the invasive behavior of bone-metastasizing breast cancer cells, via upregulation of tissue inhibitor for metalloproteinase 1 (TIMP1), and dephosphorylation of focal adhesion kinase (FAK). During tumorigenesis, stromal cells, such as fibroblasts, play important roles and several growth factors are synthesized, promoting crosstalk between different cell surface receptors. In paper III, we investigated the crosstalk between the hyaluronan receptor CD44 and the receptors for TGFβ and platelet-derived growth factor BB (PDGF-BB) in dermal fibroblasts. We found that the receptors for the three molecules form a ternary complex, and that PDGF-BB can activate the Smad pathway downstream of TGFβRI. Importantly, CD44 negatively modulated the signaling of both PDGF-BB and TGFβ. In paper IV, we studied the process by which breast cancer cells invade blood-vessels and the role of hyaluronan and CD44 in angiogenesis. Importantly, CD44, or the hyaluronan degrading enzyme hyaluronidase 2 (HYAL2), decreased the capacity of endothelial cells to form tubes in a 3D in vivo-like assay. Collectively, our studies add to the understanding of the role of hyaluronan in tumor progression.

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Leuchs, Maike Julia Martina [Verfasser]. "Hypoxie verstärkt die PDGF-vermittelte Signalübertragung in humanen pulmonal arteriellen Gefäßmuskelzellen / Maike Julia Martina Leuchs." Köln : Deutsche Zentralbibliothek für Medizin, 2012. http://d-nb.info/1025824865/34.

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Buhl, Eva M. Verfasser], Jürgen [Akademischer Betreuer] Flöge, and Ralph [Akademischer Betreuer] [Panstruga. "Die Rolle von PDGF-D in der Nierenfibrose / Eva M. Buhl ; Jürgen Flöge, Ralph Panstruga." Aachen : Universitätsbibliothek der RWTH Aachen, 2016. http://d-nb.info/1162340991/34.

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Campbell, M. "The role of PDGF-Î² receptor in high glucose-induced vascular smooth muscle cell chemotaxis." Thesis, Queen's University Belfast, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.269026.

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Adbeish, Idris S. "Clinical biochemistry of lipoproteins : altered expression of LDL-R and PDGF-A genes in hyperlipidaemia." Thesis, University of Reading, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.307805.

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McKay, Jennifer Susan. "The role of platelet-derived growth factor (PDGF) in remyelination in the central nervous system." Thesis, University of Cambridge, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.624698.

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Pereira, Angélica Costa Aranha Camacho 1976. "Efeito de um bloqueador do receptor PDGF na adipogênese de camundongos tratados com dieta hiperlipídica." [s.n.], 2011. http://repositorio.unicamp.br/jspui/handle/REPOSIP/311204.

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Orientador: Mario Jose Abdalla Saad
Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
Made available in DSpace on 2018-08-19T05:14:43Z (GMT). No. of bitstreams: 1 Pereira_AngelicaCostaAranhaCamacho_M.pdf: 3142690 bytes, checksum: 8065b10475eb506444c228857930fc87 (MD5) Previous issue date: 2011
Resumo: A obesidade é hoje considerada um problema de saúde pública. Essa condição é caracterizada pelo aumento do peso corporal, mais especificamente do tecido adiposo branco. A adipogênese (diferenciação do pré-adipócito em adipócito) é um fenômeno complexo e não muito bem caracterizado. Recentes estudos mostraram que os préadipócitos estão localizadas nas paredes dos vasos que irrigam o tecido adiposo. Estas células estão presentes exclusivamente neste tecido e expressam alguns marcadores, dentre eles o PDGFRß. O PDGFRß é um receptor tirosina quinase cujo papel na migração, proliferação e diferenciação de diversos tipos celulares tem sido extensivamente estudado. O AG1296 (6,7- dimetoxi-2-fenil-quinoxalina) é um potente inibidor do receptor PDGF, pertencente à classe da quinoxalinas. Deste modo, levando-se em consideração o papel do receptor PDGF no crescimento e proliferação celulares e o fato de que as células PDGFR_ positivas provenientes do tecido adiposo possuem alto potencial adipogênico, neste estudo investigamos o efeito do AG1296 na adipogênese de camundongos submetidos à dieta hiperlipídica e à dieta padrão. Nós também investigamos se essa inibição afetaria a sensibilidade à insulina desses grupos estudados. Para tanto, camundongos Swiss machos com seis semanas de vida foram divididos em quatro grupos: o grupo Controle que recebeu dieta padrão, o grupo C+AG1296 que recebeu dieta padrão e tratamento com AG1296, o grupo DH que recebeu dieta hiperlipídica somente e o grupo DH+AG1296 que recebeu dieta hiperlipídica e tratamento com AG1296. Peso corpóreo e ingestão alimentar foram medidos diariamente durante o tratamento (7 ou 15 dias). Através de Western blot, foram quantificadas as principais proteínas pró-adipogênicas (SREBP-1c, C/EBP? e PPAR?) e a fosforilação das principais proteínas da via da insulina (IR, IRS1 e AKT). Nossos resultados indicaram que nos animais controle, após 15 dias de tratamento com AG1296, houve uma redução nas três frações de tecido adiposo, associada a uma redução em algumas das proteínas adipogênicas, além de uma melhora na sinalização insulínica em fígado e músculo e uma redução na glicemia de jejum. Além disso, nos animais submetidos à dieta hiperlipídica, após 7 dias de tratamento com AG1296, foi possível observar uma redução nas proteínas adipogênicas e uma redução na fração epididimal do tecido adiposo. Houve também uma melhora na sinalização insulínica e na tolerância à glicose. Com isso, podemos sugerir que a inibição do PDGFRß pode ter um papel importante na adipogênese e na sinalização insulínica e pode ser um alvo potencial para prevenção da obesidade e resistência à insulina
Abstract: Obesity can be defined as a disease in which body fat is excessively accumulated. Adipogenesis is a complex and not completely known phenomenon. Recent studies showed that adipocyte progenitor cells are exclusively found in adipose tissue and express some markers like PDGFRß (Platelet-derived growth factor ß). AG1296 (6,7-dimethoxy-2-phenyl-quinoxaline) is a potent and selective inhibitor of PDGF receptor kinase. In this context, the main objective of this work was to investigate if the inhibition of PDGF receptor through AG1296 would be able to affect white adipose tissue generation in high-fat-diet-fed and standard-chow-fed mice. We also investigated if this inhibition would have an effect on the insulin sensitivity in these studied groups. For this purpose, six-week-old male Swiss mice were divided into four groups and assigned to receive the following diet and/or treatment: the control group (C) received standard rodent diet, the second group (C + AG1296) received standard rodent diet plus AG1296 (50 mg/Kg/day by gavage), the third group (HFD) received high fat diet (55% calories from fat, 29% calories from carbohydrate and 16% from protein) and the fourth group (HFD+AG1296) received high fat diet plus AG1296. Body weight and food intake were measured during the treatment (7 and 15 days). After that, tissues (epididymal, retroperitoneal and mesenteric adipose tissue, liver and muscle) were extracted and processed. Through Western blot analysis, we were able to quantify the main proteins related to adipogenesis (SREBP-1c, C/EBP? e PPAR?) and the phosphorylation of the main proteins from insulin pathway (IR, IRS1 and Akt). Our results indicated that on control mice, after 15 days of treatment with AG1296, there was a reduction on adipose fat pad, associated with reduction in some adipogenic proteins, an increase in insulin signaling in liver and muscle and a reduction in fasting plasma glucose. Futhermore, on mice fed a high fat diet, after 7 days of treatment with AG1296, it was possible to observe a reduction on adipogenesis proteins and a reduction in epididymal fat pad. Also, there was an improvement in insulin signaling pathway and in glucose tolerance. In conclusion, our results suggest that PDGFRß inhibition might have an important role in adipogenesis and in insulin signaling and could be a potential target for preventing obesity and insulin resistance
Mestrado
Biologia Estrutural, Celular, Molecular e do Desenvolvimento
Mestre em Ciências

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