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1
Tejedor, Vaquero Sonia 1988. "Influence of metabolism in the regulation of T cell differentiation." Doctoral thesis, Universitat Pompeu Fabra, 2018. http://hdl.handle.net/10803/664638.
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Glucose is a key nutrient for T cells. Despite that T cell activation is impaired when they are deprived of glucose, it has also been shown that T effector responses can be elicited in vivo in glucose-poor environments, such as the intratumoral niche, which raises the question of how these cells can maintain their function in nutrient-restricted sites. In this work, we analyzed the ability of T effector cells to be activated by pro-inflammatory polarizing conditions under limiting glucose availability, using an in vitro model in which effector Th0 cells were restimulated to secondary effector T cells in glucose deficiency (0.3 mM). We found that secondary effector T cells could express characteristic Th1 and Th17 cytokines such as IL-17A and IFNγ when exposed to low glucose, but they lost expression of IL-22. Secondary effector T cells adapted to low glucose by reducing their rate of glucose consumption and expression of glycolysis genes, although they still kept using glucose as the main fuel for ATP production. In addition, we found that glucose limitation caused a mild, progressive impairment on mTORC1 activity in these cells that explained in part the downregulation of IL-22, an mTORC1-dependent cytokine. Our results also showed that secondary effector T cells that had experienced glucose stress acquired a nutrient-trained phenotype, and when they were later restimulated under glucose sufficiency they induced an altered cytokine expression pattern with exacerbated production of IL-22 and reduced IFNγ production. Finally, we observed that effector CD4+ T cells generated in different activation contexts in vivo exhibited different patterns of glucose-sensitive genes upon restimulation ex vivo, which suggested that the context in which T effector cells are induced might be a relevant determinant in shaping different response patterns to glucose limitation upon further stimulation. Altogether, our results uncover a previously unappreciated robustness of T cells to maintain effector function under nutrient-restricted conditions, also revealing that a prior history of nutrient stress can influence future effector T cell responses.<br>La glucosa és un nutrient essencial per les cèl·lules T. Malgrat que l’activació T es veu disminuïda per la manca de glucosa, s’ha vist que respostes T efectores tenen lloc in vivo en entorns amb nivells baixos de glucosa, com són els tumors. Això planteja la incògnita de saber com aquestes cèl·lules poden mantenir les seves funcions en ambients pobres de nutrients. En aquest treball hem analitzat la capacitat de les cèl·lules T efectores (Th0) de ser activades en condicions pro-inflamatòries i nivells baixos de glucosa (0.3 mM). Hem vist que les cèl·lules T efectores secundàries poden induir citocines característiques de respostes Th1 i Th17 com la IL-17A i l’IFNγ en condicions de nivells baixos de glucosa, però perden la capacitat d’expressar la IL-22. Aquestes cèl·lules s’adapten a un entorn baix de glucosa reduint-ne el consum i reduint l’expressió de gens de la glicòlisi, malgrat tot, la glucosa segueix sent la seva principal font d’energia (ATP). A més a més, hem observat que nivells limitats de glucosa provoquen una lleu però progressiva deficiència en l’activitat d’mTORC1, necessària per la producció de la IL-22 i que explicaria en part la disminució dels nivells d’aquesta citocina. Els nostres resultats també mostren que les cèl·lules T efectores secundàries que han experimentat un estrès de glucosa adquireixen un fenotip de memòria que fa que responguin de manera alterada (producció exagerada de IL-22) a un segon estímul en presència de nivells normals de glucosa. Finalment, hem observat que les cèl·lules T CD4 efectores activades in vivo expressen diferencialment gens sensibles a glucosa quan són re-estimulades ex vivo. Això suggereix que el context d’activació d’una cèl·lula T és important per determinar la resposta d’aquestes cèl·lules a posteriors estimulacions en situació de baixa glucosa. En resum, els nostres resultats mostren que els limfòcits T son capaços de mantenir un ventall de funcions efectores en situacions de restricció de nutrients, però que el haver passat per una etapa d’estrès de nutrients pot condicionar els seus perfils d’expressió gènica en respostes efectores futures.
2
Babić, Nikolina. "Regulation of energy metabolism of heart myoblasts /." Thesis, Connect to this title online; UW restricted, 2004. http://hdl.handle.net/1773/11563.
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Mathew, Jasmin. "Keratin 8/18 regulation of hepatic cell death and metabolism." Thesis, Université Laval, 2009. http://www.theses.ulaval.ca/2009/26554/26554.pdf.
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Szkolnicka, Dagmara Maria. "MicroRNA regulation of drug metabolism in stem cell-derived hepatocytes." Thesis, University of Edinburgh, 2016. http://hdl.handle.net/1842/23421.
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The liver is a multi-functional and highly regenerative organ. While resilient, the liver is susceptible to organ damage and failure. In both the acute and chronic settings liver disease has dire consequences for health. A common cause of liver damage is adverse reactions to drugs which can lead to drug induced liver injury (DILI). This creates major problems for patients, clinicians, the pharmaceutical industry and regulatory authorities. In the context of drug overdose or serious adverse reactions, liver failure can be acute and life threatening, and in some cases require orthotopic liver transplantation. While transplantation is highly successful, such an approach has limitations and justifies basic science attempts to develop better human models to study liver injury and to develop scalable intervention strategies. With this in mind, we have studied the importance of microRNAs (miRs) in regulating human drug metabolism in pluripotent stem cell – derived hepatocytes and their potential to reduce liver toxicity in response to toxic levels of paracetamol. miRs are small non-coding RNAs that are approximately 20 - 24 nucleotides long and their major function is to fine tune gene expression of their target genes. Recently, it has been demonstrated that microRNAs play a role in regulating the first phase of drug metabolism however the second phase of drug metabolism, drug conjugation, has not been studied in detail. Drug conjugation is a crucial stage in human drug metabolism, and any alterations in this process can lead to changes in compound pharmacology, including therapeutic dose and clearance from the body. To test the importance of miRs in regulating phase II drug metabolism we opted to study the metabolism of a common used analgesic, paracetamol. When taken in the appropriate amounts paracetamol is modified by sulfotransferases (SULTs) and UDP - glucuronosyltransferases (UGTs) and removed from the body without organ damage. However, when paracetamol is taken above the recommended dose it is metabolised by phase I enzymes to generate a toxic intermediate N-acetyl-p-benzoquinone imine (NAPQI), which if untreated can lead to massive hepatocyte cell death and liver failure, placing the patient in a life threatening situation. In order to promote non-toxic drug metabolism, in the context of drug overdose, we employed candidate miRs to regulate different parts of the paracetamol metabolism pathway. In summary, we have focused on studying human drug metabolism in the major metabolic cell type of the liver, the hepatocyte. We have identified a novel microRNA (called miR-324-5p) which regulates phase II drug metabolism and reduces cell cytotoxicity. Additionally, a supportive role of anti-microRNA- 324 in response to fulminant plasma collected from paracetamol overdose patients is also observed. The findings of this project are novel, provide proof of concept and exemplify the power of stem cell based models to identify new approaches to treating human liver damage.
5
Mukherjee, Abir. "ROLE OF LYSOPHOSPHATIDIC ACID IN REGULATION OF CANCER CELL METABOLISM." VCU Scholars Compass, 2012. http://scholarscompass.vcu.edu/etd/391.
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The simplest phospholipid, lysophosphatidic acid (LPA), is a heat stable component of serum known for its proliferative and migratory activities in cancer cells. Strong evidence suggests that LPA production and expression of its receptors are dysregulated in multiple human malignancies. The mechanism behind LPA-mediated tumor cell growth and oncogenesis remains poorly understood. In this thesis project I used ovarian and other cancer cells as a model system to examine the hypothesis that LPA present in the tumor microenvironment is a pathophysiological determinant of hyperactive de novo lipogenesis and aerobic glycolysis, two hallmarks of cancer cells. We demonstrated that LPA induced proteolytic activation of sterol regulatory element binding proteins (SREBPs) in a cancer specific manner, leading to activation of the SREBP-FAS (fatty acid synthase) lipogenic pathway. Treatment of cancer cell lines with LPA also led to dephosphorylation and inhibition of AMP-activated kinase (AMPK), thereby activating acetyl CoA carboxylase (ACC). Moreover, these effects of LPA were mediated by LPA2, a receptor subtype overexpressed in multiple cancers, providing an explanation for the cancer specific regulation of FAS and ACC by LPA. Downstream of the LPA2 receptor, we identified the Gα12-Rho-Rock pathway to activate SREBPs and the Gαq-PLC (phospholipase C) pathway to inactivate AMPK. Consistent with LPA mediated activation of the key lipogenic enzymes FAS and ACC, LPA stimulated de novo lipid synthesis via LPA2, leading to accumulation of intracellular triacylglycerol and phospholipids. Pharmacological and molecular inhibition of LPA2, FAS or ACC attenuated LPA-dependent cell proliferation, indicating that upregulation of lipid synthesis is an integral component of the proliferative response to LPA. In further support of this, downregulation of LPA2 expression led to dramatic inhibition of anchorage-dependent and –independent growth of ovarian cancer cells. To support increased biomass generation, rapidly proliferating cancer cells enhance carbon influx by activating glycolysis. In the next part of the study, we investigated if LPA signaling was also involved in activating aerobic glycolysis in cancer cells. LPA indeed activated glycolysis in ovarian and other cancer cells but failed to elicit this response in non-transformed cells, suggesting a cancer specific role of LPA in regulation of glucose metabolism. While LPA had no effect on glucose uptake, we found that LPA altered expression of multiple genes involved in glucose metabolism. The most significant observation was that LPA treatment dramatically upregulated expression of HK-2, one of the rate-limiting glycolytic enzymes. We explored the underlying mechanism and found that LPA activates HK-2 transcription through LPA2-mediated activation of SREBP-1. Two sterol regulator elements (SREs) on the human HK-2 promoter were identified to be responsible for LPA activation of the promoter. DNA pulldown and chromatin immunoprecipitation assays confirmed that SREBP-1 bound to these SREs in LPA-treated cells. Although in ovarian cancer cells, LPA treatment also stabilized Hif-1α protein, an established activator of HK-2 and glycolysis, LPA-regulated HK-2 expression and glycolysis was largely independent of Hif-1α. These results established that LPA stimulates glycolysis via the LPA2-SREBP-HK-2 cascade in neoplastic cells. Taken together, this dissertation provides the first evidence for regulation of cancer cell metabolism by LPA. The results indicate that LPA signaling is causally linked to lipogenic and glycolytic phenotypes of cancer cells. Therefore, targeting the key LPA2 receptor could offer a novel and innovative approach to blocking tumor-specific metabolism.
6
Syal, Charvi. "Epigenetic Regulation of Lipid Metabolism in Neural Stem Cell Fate Decision." Thesis, Université d'Ottawa / University of Ottawa, 2019. http://hdl.handle.net/10393/38706.
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Bioactive lipids have emerged as prominent regulators of neural stem and progenitor cell (NPC) function under both physiological and pathological conditions. However, how lipid metabolism is regulated, and its role in modulation of NPC function remains unknown. In this regard, my study defines a novel epigenetic pathway that regulates lipid metabolism to determine NPC proliferation versus differentiation. Specifically, I show that activation of an atypical protein kinase C (aPKC)-mediated Ser436 phosphorylation of CREB binding protein (CBP) by aging, metformin stimulation and continued passaging in vitro, represses expression of monoacylglycerol lipase (Mgll) to promote neuronal differentiation of adult NPCs. Mgll, a lipase that hydrolyzes the endocannabinoid 2-arachidonoyl glycerol (2-AG) to produce arachidonic acid (ARA), is thus a key regulator of two critical bioactive lipid signaling pathways in the brain and a potential modulator of NPC function. I observed elevated Mgll levels, concomitant with neuronal differentiation deficits in both the lateral ventricle sub-ventricular zone (SVZ) and the hippocampal subgranular zone (SGZ) NPCs of phospho-null CBPS436A mice, that lack a functional aPKC-CBP pathway. Genetic knockdown of Mgll or inhibition of Mgll activity rescued these neuronal differentiation deficits. In addition, I found that CBPS436A SVZ NPCs exhibit enhanced proliferation at the expense of differentiation as an outcome of increased Mgll levels in culture. Interestingly, I also observed that SVZ NPCs from an Alzheimer’s disease (AD) model, the 3xTg mice, closely resemble CBPS436A NPC behaviour in culture. 3xTg NPCs exhibit attenuation of the aPKC-CBP pathway, which is associated with elevated Mgll expression and increased NPC proliferation at the expense of neuronal differentiation. Reactivation of the aPKC-CBP mediated-Mgll repression in 3xTg AD NPCs mitigates their differentiation deficits. These findings implicate Mgll as a critical switch that regulates NPC function by altering bioactive lipid signaling (2-AG versus ARA). They demonstrate that the aPKC-CBP mediated Mgll repression is essential for normal NPC function, and that when perturbed in AD, it causes impaired NPC function to generate fewer neurons, contributing to AD predisposition.
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Ng, Shyh Chang. "Regulation of Stem Cell Metabolism by the Lin28/let-7 Axis." Thesis, Harvard University, 2013. http://dissertations.umi.com/gsas.harvard:11217.
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My PhD thesis is focused on two fundamental aspects of stem cell metabolism: (1) the role of Lin28 in programming stem cell metabolism, and (2) how metabolism in turn fuels and governs pluripotency. Our studies led us to discover that the stem cell factor Lin28a promotes gigantism by enhancing glucose metabolism in mice, coinciding with discoveries that LIN28B polymorphisms influence height variation in human GWAS. Subsequently, we discovered that the Lin28/let-7 pathway controls glucose metabolism by orchestrating the upregulation of multiple insulin-PI3K-mTOR components, particularly in skeletal muscle progenitors. Since let-7 accumulates with aging, our discoveries suggest that let-7 could represent a new drug target for treating insulin resistance and type 2 diabetes during aging. During these studies, we also observed that Lin28a enhances tissue regeneration in adulthood. Regeneration capacity has long been known to decline with aging, but why juvenile organisms show enhanced tissue repair had remained unexplained. We found that Lin28a reactivation improved the regrowth of skin, hair, cartilage, bone and mesenchyme after injuries. Let-7 repression was necessary but insufficient to explain these phenotypes. In parallel, Lin28a bound to and enhanced the translation of mRNAs for several oxidative enzymes, thereby increasing OxPhos. Lin28a-mediated tissue repair was negated by OxPhos inhibition, whereas a pharmacologically-induced increase in OxPhos promoted wound repair. Thus, Lin28a enhanced tissue regeneration in adults by reprogramming cellular bioenergetics. My interest in the central principles of stem cell metabolism also led us to map the metabolic pathways associated with pluripotency during iPS reprogramming and Lin28/let-7 perturbation. Surprisingly, we found that Thr-Gly-S-adenosylmethionine (SAM) metabolism consistently showed the best correlation with pluripotency. 13Carbon isotope metabolomics further revealed that Thr was catabolized to generate Gly and acetyl-CoA, and ultimately SAM - essential for all methylation reactions. Thr is required for SAM and histone H3K4 methylation in mouse ESCs, thus regulating the open euchromatin and pluripotency of ESCs. Our study shed light on a novel amino acid pathway in stem cells, and demonstrated that metabolic conditions can direct cell fate. In summary, my work has helped us to understand how we can reprogram and manipulate metabolic networks to regulate stem cell homeostasis.
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Mofarrahi, Mahroo. "Regulation of skeletal muscle satellite cell proliferation by NADPH oxidase." Thesis, McGill University, 2007. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=111521.
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Skeletal satellite cells are adult stem cells located among muscle fibers. Proliferation, migration and subsequent differentiation of these cells are critical steps in the repair of muscle injury. We document in this study the roles and mechanisms through which the NAPDH oxidase complex regulates skeletal satellite cell proliferation. The NADPH oxidase subunits Nox2, Nox4, p22phox, p47phox and p67 phox were detected in primary human and murine skeletal muscle satellite cells. In human satellite cells, NADPH oxidase-fusion proteins were localized in the cytosolic and membrane compartments of the cell, except for p47 phox, which was detected in the nucleus. In proliferating subconfluent satellite cells, both Nox2 and Nox4 contributed to O2- production. However, Nox4 expression was significantly attenuated in confluent cells and in differentiated myotubes. Proliferation of satellite cells was significantly reduced by antioxidants (N-acetylcysteine and apocynin), inhibition of p22phox expression using siRNA oligonucleotides, and reduction of Nox4 and p47phox activities with dominant-negative vectors resulted in attenuation of activities of the Erk1/2, PI-3 kinase/AKT and NFkappaB pathways and significant reduction in cyclin D1 levels. We conclude that NADPH oxidase is expressed in skeletal satellite cells and that its activity plays an important role in promoting proliferation of these cells.
9
Aitchison, Robert E. D. "Mammary cell cyclic AMP : regulation of breakdown and influence on protein phosphorylation." Thesis, University of Glasgow, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.303363.
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Beauchamp, Pascal. "The functional role of the RNA-binding protein HuR in the regulation of muscle cell differentiation /." Thesis, McGill University, 2008. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=111586.
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Muscle tissue development (myogenesis) involves the formation of specific fibers (myotubes) from muscle cells (myoblasts). For this to occur, the sequential expression of Myogenic Regulatory Factors (MRFs), such as MyoD and myogenin, is required. The expression of these MRFs is regulated posttranscriptionally by the RNA-binding protein HuR, whereby HuR associates with the 3'-untranslated regions of MyoD and myogenin mRNA, leading to a significant increase in their half-lives. Here we show that the cleavage of HuR by caspases at the aspartate (D) 226 residue is one of the main regulators of its pro-myogenic function. This proteolytic activity generates two cleavage products (CPs), HuR-CP1 and HuR-CP2, that differentially affect the myogenic process. Myoblasts overexpressing HuR-CP1 or the non-cleavable mutant of HuR, HuRD226A, are not able to engage myogenesis, while overexpressing HuR-CP2 enhances myotube formation. HuR-CP2 but not -CP1 promotes myogenesis by stabilizing the MyoD and myogenin mRNAs to the same levels as wt-HuR. Conversely, the inhibitory effects of HuR-CP1 and HuRD226A depend on their abilities to associate during myogenesis with the HuR import receptor, Trn2, leading to HuR accumulation in the cytoplasm. Therefore, we propose a model whereby the caspase-mediated cleavage of HuR generates two CPs that collaborate to regulate myogenesis; HuR-CP1 by interfering with the Trn2-mediated import of HuR and HuR-CP2 by participating in the stabilization of mRNAs encoding key MRFs.
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Nilsson, Per. "Allosteric Regulation of mRNA Metabolism : -Mechanisms of Cap-Dependent Regulation of Poly(A)-specific Ribonuclease (PARN)." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-8647.
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Lin, Weiyang. "Phospholipid metabolism in the MCF-7 cell cycle, regulation of phosphatidylcholine accumulation." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape2/PQDD_0015/NQ53065.pdf.
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Rainer, Roman Josef. "Identification of differential regulation in central carbon metabolism between related cell lines." Doctoral thesis, Humboldt-Universität zu Berlin, 2020. http://dx.doi.org/10.18452/22117.
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Darmkrebszellen und T-Zellen regulieren ihren zentralen Kohlenstoffmetabolismus um
ihren anabolen Bedarf zu erfüllen. Tumorzellen mit einer KRAS- oder BRAF-Mutation
zeigen ein schnelles Wachstum, welches eine Umprogrammierung des Metabolismus vor
aussetzt. Der mitochondriale T-Zellen-Aktivierungsinhibitor (TCAIM) ist bekannt dafür
die mitochondriale Zellstruktur zu beeinflussen. Der Einfluss auf den Metabolismus nicht
klar.
In dieser Arbeit präsentiere ich erstmalig ein mathematische Model des zentralen Kohlen
stoffmetabolismus in Darmkrebszellen und T-Zellen. Mithilfe dieses Modells analysiere
ich, wie sich die Regulation in ähnlichen Zelllinien unterscheidet. In Bezug auf die Darm
krebszellen vergleiche ich BRAF-(CaCO2-BRAFV600E), KRAS-(CaCO2-KRASG12V) mu
tierte Zelllinien mit einer Basiszelllinie (CaCO2-control) und zeige, dass der Kohlenstoff
metabolismus in BRAF-mutierten Zellen im Vergleich zu den beiden übrigen Zelllinien
herabreguliert ist. Das Modell bestätigt außerdem, dass der Monocarboxylattransporter
(MCT) in den Darmkrebszellen eine wichtige Rolle, insbesondere in den KRAS mu
tierten Zellen, spielt. In T-Zellen zeigt der Vergleich von Wildtypzellen (CD8 T-Zellen)
mit TCAIM homozygoten Zellen (TCAIM homozygote CD8 T-Zellen), dass der Kohlen
stoffmetabolismus in zweiteren überwiegend herabreguliert und weniger aktiv ist. Diesen
Effekt konnte ich durch die Analyse von RNASeq-Daten der jeweiligen Zelltypen bestä-
tigen. Des Weiteren stelle ich fest, dass sich der Tricarbonsäurezyklus umkehrt, wenn
durch die Glykolyse nicht ausreichend Laktat exportiert und die Biomasseproduktion
unterstützt werden kann.
Meine Arbeit stellt damit insgesamt einen neuartigen Ansatz zur Integration von Meta
bolomik und RNAseq Daten dar, um die Regulation des zentralen Kohlenstoffmetabo
lismus zu verstehen.<br>Colon cancer cells and T cells regulate central carbon metabolism to meet their anabolic
needs. In KRAS and BRAF tumors, metabolic reprogramming is a premise to support
rapid proliferation. In T cells, the mitochondrial T cell activation inhibitor (TCAIM)
is known to affect mitochondrial morphology but its effect on cellular metabolism is
not well understood. Via mathematical modelling, I investigate the differential regulation of closely related cell lines. I present the first mathematical model for colon cancer and T cell metabolism, unraveling differential regulation between related cell lines.
The model shows that CaCO2-BRAFV600Ecells are mostly downregulated compared to
CaCO2-KRASG12Vand CaCO2-control. Additionally, it demonstrates the critical role
of monocarboxylate transporter (MCT), especially for CaCO2-KRASG12V. Concerning T cells, I compare wild-type T cells to homozygous TCAIM T cells. This unveils
that TCAIM homozygous cells have a mostly downregulated TCA cycle, validated by
RNASeq data, and are less metabolically active than wild-type T cells. Furthermore,
if the glycolytic flux is not sufficient to support lactate export and biomass production,
the model reveals that the TCA cycle is reversed as it requires less regulation. Taken
together, this work presents a novel approach to integrate data referring to metabolic
and genetic regulation of metabolism. On this basis, we can now better discriminate the
metabolic capacity of CaCO2-control, CaCO2-BRAFV600E, CaCO2-KRASG12V, wildtype CD8 T cells, and homozygous TCAIM CD8 T cells.
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Koseoglu, Mehmet Murat Marzluff William F. "Cell cycle regulation of the stem loop binding protein a key regulator in histone mRNA metabolism /." Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2007. http://dc.lib.unc.edu/u?/etd,2081.
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Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2007.<br>Title from electronic title page (viewed Feb. 17, 2009). "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Biology Graduate Studies in Molecular, Cell, and Developmental Biology." Discipline: Biology; Department/School: Biology.
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Tomac, Andreas C. "Glial cell line-derived neurotrophic factor : expression patterns, neuronal transport, regulation, effects and receptor dependence /." Stockholm, 1998. http://diss.kib.ki.se/search/diss.se.cfm?19980618toma.
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Atmosukarto, Ines Irene Caterina. "Biochemical and genetic approach to the characterisation of Tec function in the mouse." Title page, contents and summary only, 2001. http://web4.library.adelaide.edu.au/theses/09PH/09pha881.pdf.
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Copy of author's previously published work inserted. Includes bibliographical references (leaves 160-182). Concentrates mainly on the characterisation of the molecular mechanism of action of the tec protein tyrosine kinase using biochemical and genetic approaches.
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Pursglove, Sharon Elizabeth. "Biophysical analysis of Tec Kinase regulatory regions : implications for the control of Kinase activity." Title page, contents and summary only, 2001. http://web4.library.adelaide.edu.au/theses/09PH/09php9863.pdf.
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Secinaro, Michael Anthony. "The Contribution Of Metabolism To The Regulation Of Caspase Activity And Cell Death In T Lymphocytes." ScholarWorks @ UVM, 2019. https://scholarworks.uvm.edu/graddis/1000.
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During an immune response, T cell activation is mirrored by a dramatic metabolic shift from oxidative phosphorylation to glycolysis. The upregulation of glycolysis allows the cell to generate the molecules needed to rapidly proliferate and to synthesize effector molecules. The resolution of the T cell response is characterized by equally fast death of most effector T cells. The remaining T cells shift back to oxidative phosphorylation, allowing the cell to survive as a memory T cell. The upregulation of glycolysis and proliferation during the effector phase is paralleled by an increased sensitivity to T cell receptor restimulation-induced cell death (RICD). Whereas cellular metabolism and cell death are important in the proper function and response of T cells, it is not clear how metabolism regulates susceptibility to cell death, nor whether T cell proliferation and contraction are directly connected. The work presented in this dissertation provides a mechanistic link between T cell proliferation and contraction by demonstrating the regulation of caspase-3 activity by the metabolic state of T cells.
In effector T cells, the cytokine interleukin (IL)-2 mediates the upregulation of glycolysis, while IL-15 induces oxidative phosphorylation and a memory-like state. IL-2 is known to sensitize T cells to RICD, while IL-15 reduces RICD and increases survival. This results from the ability of IL-2 and glycolysis to increase caspase-3 activity, whereas IL-15 induces the opposite phenotype. Activation of caspase-3 during glycolysis is mediated through clustering in lipid rafts in the plasma membrane. IL-15 is shown to inactivate caspase-3 through the posttranslational modification of protein glutathionylation, which is mediated by ROS generation in the mitochondria as a by-product of oxidative phosphorylation.
We further observe that glycolysis parallels the reduced activity of the electron transport chain and oxidative phosphorylation, further increasing caspase-3 activity. This is mediated by the decreased expression of electron transport chain complexes and an increase in expression of the negative regulator of complex I, methylation-controlled J protein (MCJ). IL-15 promotes reduced expression of MCJ by its methylation. Similar to IL-15-cultured T cells, MCJ-deficient T cells manifest reduced glycolysis, caspase-3 activity, and RICD. Collectively, these findings demonstrate an adaptation that links metabolism to both cell proliferation and cell death to safeguard that proliferating cells do not escape regulation that could result in autoimmune disease or lymphomas.
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Chenery, Alistair Lee. "Regulation of mucosal T cell responses by intestinal helminths and retinoic acid metabolism." Thesis, University of British Columbia, 2016. http://hdl.handle.net/2429/57723.
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Mucosal immune diseases such as asthma and inflammatory bowel disease are associated with major environmental factors - diet, geography, hygiene, infections - that contribute to disease risk. The mucosal immune system is in direct contact with the external environment and must balance protective immune responses with tolerance to innocuous antigens. Since chronic inflammation at mucosal sites depends on a diverse set of T cell-driven responses, understanding the factors that regulate mucosal T cell differentiation and function is key to developing better treatments to a variety of inflammatory diseases. Further, immunological cross-talk can occur between mucosal organs such as the intestine and the lung, but the role of T cells in this cross-talk is poorly defined. The work herein investigates the effect of external factors, specifically intestinal infections and dietary immunomodulators, on mucosal T cell responses in the context of inflammation in the intestine and the lungs. Using a mouse model of infection with the intestinal helminth Trichuris muris, I show infection-mediated alterations in the lung microenvironment that can protect against murine models of allergic airway inflammation. I further show that intestinal T. muris infection has a systemic effect on hematopoiesis in the bone marrow. In other studies, I examine the role of the dietary vitamin A metabolite, retinoic acid, on T cell function during intestinal inflammation. Specifically, I investigate how metabolism of retinoic acid by the enzyme Cyp26b1 modulates T cell differentiation and function and show that Cyp26b1 controls regulatory T cell and T helper 17 differentiation in vitro. Further, I posit a role of Cyp26b1 in regulating effector T cell function in vivo using a murine model of T cell-driven inflammatory bowel disease. Thus, the results presented here provide further insight into helminth-mediated immune regulation, intestine-to-lung mucosal immune crosstalk, and dietary immunomodulation that regulate mucosal T cell responses.<br>Medicine, Faculty of<br>Pathology and Laboratory Medicine, Department of<br>Graduate
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Ding, Min Judd Robert L. "Regulation of glucose metabolism in a hepatic and muscle cell line by adiponectin." Auburn, Ala., 2005. http://hdl.handle.net/10415/1263.
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Thwe, Phyu Myat. "Characterizing The Role And Regulation Of Glycogen Metabolism In Dendritic Cell Immune Responses." ScholarWorks @ UVM, 2018. https://scholarworks.uvm.edu/graddis/935.
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Dendritic cells (DCs) are the most potent professional antigen presenting cells (pAPCs) of the immune system and play a fundamental role in coordinating innate and adaptive immune responses. Through the expression of a wide array of pattern recognition receptors (PRRs), such as toll-like receptors (TLRs), DCs recognize a variety of microbial pathogens and infectious stimuli. Stimulation of DCs through TLR ligation results in a rapid series of activation-associated events, termed "maturation," which include the upregulation of surface co-stimulatory molecule expression, inflammatory cytokine secretion, and stimulation of naïve T cells via antigen presentation by MHC molecules.
Activation of DCs through TLRs is coupled with an increased metabolic demand fulfilled by a rapid change in DC glucose metabolism and characterized by increased aerobic glycolysis rates. TLR-driven glycolytic reprogramming plays an essential role in generating building blocks required for high level protein synthesis associated with maturation. Although glucose imported from extracellular environments has been broadly considered as the major driver of glycolytic metabolism in immune cells, the contributions of intracellular glucose stores to these processes are not well-defined. The role of intracellular stores of glucose, in the form of glycogen, is widely appreciated in non-immune systems. However, very little is known about the implication of glycogen metabolism in DC immune responses. This work unveils the role and potential regulatory mechanisms of glycogen metabolism in support of DC effector function.
The first part of this work primarily focuses on our characterization of the role of glycogen metabolism in early DC activation responses; while in the last chapter, we describe a potential regulatory mechanism of DC glycogen metabolism by activation-associated nitric oxide (NO) production. In this work, we tested the overarching hypothesis that DC-intrinsic glycogen metabolism supports the early glycolytic reprogramming required for effector responses and that nitric oxide can regulate this metabolism. We demonstrate that DCs possess the enzymes required for glycogen metabolic machinery and that glycogen metabolism supports DC immune effector response, particularly during early activation and in nutrient-limited environments. More importantly, we uncover a very intriguing metabolic phenomenon, in which DCs engage in the differential metabolic pathways driven by carbons derived distinctively from glycogen and free glucose. Our studies present the fundamental role and regulatory mechanisms of DC-intrinsic glycogen metabolism and underline the differential utilization of glycogen and glucose metabolism to support their effector responses. Overall, this work adds to a growing field of immuno-metabolism an improved understanding of an intricate layer of metabolic mechanisms that immune cells undertake in response to immune stimuli.
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Fultz, Kimberly Elizabeth. "APC-dependent regulation of polyamine metabolism and apoptosis in human colon tumor cells." Diss., The University of Arizona, 2002. http://hdl.handle.net/10150/280176.
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Mutation/deletion of the adenomatous polyposis coli (APC) tumor suppressor gene in germline cells of rodents and humans is associated with increased intestinal activity of ornithine decarboxylase (ODC), the first enzyme in polyamine synthesis, and intestinal neoplasia. To study the role of APC in signaling ODC expression, the human colon tumor cell line HT29 (wtAPC -/-) was stably transfected with a zinc-inducible wild-type APC gene. Addition of ZnCl2 to HT29-APC cells increased wild-type APC protein and Mad1 RNA and protein, and decreased levels of c-myc and ODC RNA and protein, relative to these parameters in HT29 cells transfected with the same plasmid containing the beta-galactosidase (betaGal) gene in place of APC. Upon induction of APC expression, ODC promoter activity and RNA levels were suppressed. To examine the role of APC-dependent regulation of ODC, the two sets of E-boxes were analyzed. When the E-box domain in the 5' flanking region of the ODC gene was mutated, ODC promoter activity was unaffected by wild-type APC expression. Antisense, but not missense, c-myc oligonucleotides decreased ODC activity in HT29 cells expressing mutant APC. These results indicate that APC expression can inhibit ODC via the 5' E-box. Using the cell model previously described, APC selectively represses the ODC A allele, apparently through selective binding of Mad1. These results demonstrate that wild-type APC suppresses c-myc and activates Mad1 expression in HT29 colon-derived cells. Treatment of Min mice with the ODC inhibitor, difluoromethylornithine (DFMO), suppresses intestinal polyamine contents and intestinal tumorigenesis. The data presented in this dissertation indicate that ODC is a modifier of APC-dependent signaling in intestinal cells and tissues. Apoptosis is significantly reduced in both the small intestines and colons of Min (multiple intestinal neoplasia) mice when compared to normal littermates. Apoptotic indices can be restored by treating the mice with alpha-difluoromethylornithine (DFMO). DFMO is a specific, irreversible inhibitor of ornithine decarboxylase (ODC), the first enzyme in polyamine biosynthesis. These results indicate that APC induces apoptosis via the mitochondrial pathway rather than through the death receptor pathway. APC also affects a variety of other proteins involved in the regulation of apoptosis including transcription factors (i.e., ets2, FKHR, JunB, etc.) and bcl-2 (i.e., Bcl-xL) family members. The multiple levels at which APC functions suggest a variety of possible targets for the prevention and treatment of colon cancer. (Abstract shortened by UMI.)
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Faulkner, Ashton. "Regulation of endothelial cell metabolism by agonist-activated PPAR? : implications for angiogenesis-related activity." Thesis, Royal Veterinary College (University of London), 2017. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.731287.
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Waddington, Kirsty Elizabeth. "Regulation of membrane lipid metabolism and immune cell function by the nuclear receptor LXR." Thesis, University College London (University of London), 2018. http://discovery.ucl.ac.uk/10054993/.
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Liver X receptors (LXRs) are transcription factors with a critical role in multiple lipid metabolic pathways, and a broad range of effects on inflammatory and immune responses. I hypothesised that LXRs modulate CD4+ T cell function by regulating plasma membrane lipid rafts- highly ordered cholesterol and glycosphingolipid (GSL) enriched regions important for T-cell antigen receptor (TCR) signalling. Importantly, the GSL biosynthesis enzyme UGCG was identified as a novel LXR target gene in multiple human immune cell subsets. In CD4+ T cells, LXR activation with the synthetic ligand GW3965 regulated both cholesterol and glycosphingolipid metabolism, which resulted in reduced plasma membrane lipid order and altered responses to TCR activation. Changes in the kinetics and distribution of membrane lipid order at the immune synapse led to accumulation of TCR-proximal signalling molecule Lck at the synapse periphery. Subsequently, tyrosine phosphorylation of signalling and adapter proteins was altered. Ultimately, this was associated with an altered profile of T cell cytokine production and reduced T cell proliferation. I further hypothesised that LXR signalling may be dysregulated in CD4+ T cells from patients with the autoimmune rheumatic disease systemic lupus erythematosus (SLE), since defects in lipid raft-associated signalling have previously been identified in immune cells from SLE patients. Multiple changes in lipid metabolism were detected. However, LXR target gene expression and responses to LXR activation were only modestly perturbed. Instead, IFN response coincided with changes in expression of lipid metabolism genes both ex vivo, and in response to SLE patient serum. In summary, I have uncovered a novel action of LXR that involves modulation of lipid raft-associated cholesterol and GSLs in CD4+ T-cells. This could have important implications in diseases involving dysregulated T cell function including autoimmunity, cancer and atherosclerosis.
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McCarthy, Michael Thomas. "Mechanisms of NKG2D ligand regulation." Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:69de3276-0b1e-4174-9309-988242468682.
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Background: The NKG2D ligands are a set of cell surface proteins, the expression of which can make cells susceptible to immunity mediated by NKG2D receptor expressing cells, which include NK cells, CD8<sup>+</sup> αβ T cells and γδ T cells. The NKG2D ligands are known to be expressed in distinct settings, including viral infection, cancer, T cell activation, and cellular proliferation, settings also tightly associated with Warburg metabolism. The molecular events which determine NKG2D ligand expression status are unknown. Aims: We aim to enhance understanding of the deterministic molecular events that control NKG2D ligand expression. Specifically, to explore the relationship between Warburg metabolism and NKG2D ligand expression in cell line and physiological models, and second, to identify open chromatin elements at NKG2D ligand loci, and develop computational methods to analyse this data. Methods: We use a range of molecular biology techniques to delineate the role of glucose metabolism in NKG2D ligand expression in a HEK293T cell model. We develop a physiological CMV-primary fibroblast model of NKG2D ligand induction to validate our key findings. We adapt, optimise and validate a DNaseI-seq protocol, to define open chromatin sites at the NKG2D ligand loci. We develop a data analysis `pipeline', including our own peak-finding software (“PeakHunter"), to identify open chromatin sites in the data. Key results: Glucose drives NKG2D ligand expression. This effect requires cellular uptake and metabolism of glucose. Purine nucleotides are a key glucose metabolite for this effect, and purine nucleosides are sufficient to induce NKG2D ligand expression in our HEK293T model. We have identified the open chromatin sites at the NKG2D loci in MCF7 breast cancer cells, and optimised and validated this protocol. Finally we have developed “PeakHunter" a multifunctional software tool for mapped DNaseI-seq data analysis. Conclusions: Glucose and its contribution to purine metabolism play a central role in the induction of NKG2D ligand expression in physiological settings. The influence of glucose leads to significant alterations in cellular NKG2D-dependent immunogenicity. PeakHunter is a useful tool for analysis of mapped DNaseI-seq data.
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Crosby, Priya. "Metabolic regulation of circadian timekeeping." Thesis, University of Cambridge, 2017. https://www.repository.cam.ac.uk/handle/1810/269019.
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Circadian rhythms are self-sustained endogenous biological oscillations with a period of approximately 24 hours. These rhythms are observed widely across kingdoms and at all levels of biological scale. Recent work has shown there to be circadian variation in metabolism, both at the organismal and cellular level. It has also been posited that rhythmic production of metabolites might be essential for maintenance of circadian rhythmicity within cells, even in the absence of nascent transcription. The first portion of this thesis investigates the contribution of primary carbohydrate metabolism to cellular timekeeping, with particular emphasis on the pentose phosphate pathway. I also describe and validate a new 13C labelling technique for accurate determination of the relative flux through early primary metabolic pathways. This is accompanied by the development and optimisation of a microfluidic system for long-term perfused tissue culture, which allows for longitudinal study of metabolic flux within the same population of cells with simultaneous recording of clock gene activity. This perfused system provides several advantages over static tissue culture. The second portion considers the effects of the metabolic hormone insulin on circadian rhythmicity, both at the level of the cell and of the whole organism. It shows that administration of insulin is sufficient to shift the phase of circadian gene expression and elicits induction of clock protein PER2. Strikingly, manipulation of insulin signalling is sufficient to determine all the essential parameters of the cellular clock (phase, period and amplitude) in a dose-dependent but glucose independent fashion. Using pharmacological and genetic approaches, a molecular explanation for this effect is determined. This data suggests that insulin is a primary determinant of rhythms in peripheral tissues and is most likely a major signal for circadian entrainment to feeding in mammals, for which I now propose a mechanistic basis.
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Schuster, Susanne. "The NAMPT-mediated NAD salvage pathway in cancer cell metabolism and its regulation by resveratrol." Doctoral thesis, Universitätsbibliothek Leipzig, 2015. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-173401.
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Nicotinamide adenine dinucleotide (NAD) is a key regulator of several metabolic and signaling pathways that are relevant in cancer cell survival. Cancer cells have an increased energy demand associated with an increased NAD turnover. Nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme of the NAD salvage pathway, plays a crucial role in maintaining the intracellular NAD levels and in regulating the activity of NAD-dependent enzymes, such as sirtuins (SIRTs). The inhibition of NAMPT activity and the use of phytochemicals, such as resveratrol, represent novel therapeutic approaches in cancer therapy. Based on these facts, this thesis aimed to investigate (1) the chemotherapeutic potential and molecular mechanisms of FK866, a specific NAMPT inhibitor, and resveratrol on hepatocarcinoma cells and to find out whether there are differences compared to primary human hepatocytes; (2) to address the impact of NAMPT inhibition on the energy metabolism in cancer cells; and (3) to investigate the roles of NAMPT and SIRT1 in resveratrol´s mode of action and chemotherapeutic effects. This work demonstrates that FK866 and resveratrol possess potent chemotherapeutic effects in hepatocarcinoma cells which were absent in human hepatocytes. Hepatocarcinoma cells display a dysregulation in the AMP-activated kinase (AMPK)/mammalian target of rapamycin (mTOR) signaling as well as in the NAMPT-mediated NAD salvage pathway compared to human hepatocytes. FK866-induced NAMPT inhibition induces ATP depletion associated with AMPK activation and mTOR inhibition whereas resveratrol induces caspase3-mediated apoptosis that is not dependent on NAMPT and SIRT1 function. NAMPT and SIRT1 are differentially regulated by resveratrol in hepatocarcinoma cells and human hepatocytes. This work also reveals that resveratrol activates p53-induced cell cycle arrest in hepatocarcinoma cells which is partly mediated by SIRT1 inhibition. In summary, this thesis provides new insight into the role of the NAMPT-mediated NAD salvage pathway in energy metabolism and characterized FK866 and resveratrol as promising potential chemotherapeutic agents for treatment of hepatocellular carcinoma.
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Rainer, Roman Josef [Verfasser]. "Identification of differential regulation in central carbon metabolism between related cell lines / Roman Josef Rainer." Berlin : Humboldt-Universität zu Berlin, 2020. http://d-nb.info/1222028697/34.
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Taruttis-Glagoleff, Franziska [Verfasser], and Rainer [Akademischer Betreuer] Spang. "Modeling MYC-dependent regulation of gene expression and cell metabolism in B-cell lymphomas / Franziska Taruttis-Glagoleff ; Betreuer: Rainer Spang." Regensburg : Universitätsbibliothek Regensburg, 2021. http://d-nb.info/1230135979/34.
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English, Tamara Erica Carleton University Dissertation Biology. "Differential gene expression in response to freezing and anoxia in the intertidal marine gastropod, littorina littorea." Ottawa, 2000.
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Okemo, Pauline Asami. "Regulation of plant programmed cell death by energy metabolism in the Australian resurrection grass Tripogon loliiformis." Thesis, Queensland University of Technology, 2020. https://eprints.qut.edu.au/205617/1/Pauline_Okemo_Thesis.pdf.
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Recent studies have shown that T.loliiformis, a resurrection grass, may use the tight regulation of PCD pathways like autophagy to facilitate desiccation tolerance. The aim of this project was to further investigate the mechanisms that T.loliiformis use to suppress PCD and survive prolonged periods of water deficit. This study provides additional insight on how T.loliiformis attains desiccation tolerance that significantly contributes to our knowledge on the pathways and mechanisms used by resurrection plants. The findings from this study will hopefully be employed to harness drought tolerant properties of resurrection grasses to improve the resilience of economically important crops.
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Purcell, Robert. "Regulation of endothelial cell function by omega-3 fatty acids and their oxygenated metabolites : mediators of vascular protection?" Thesis, Royal Veterinary College (University of London), 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.701662.
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James, Andrew. "Metabolic regulation of the plasma membrane calcium pump in pancreatic ductal adenocarcinoma." Thesis, University of Manchester, 2015. https://www.research.manchester.ac.uk/portal/en/theses/metabolic-regulation-of-the-plasma-membrane-calcium-pump-in-pancreatic-ductal-adenocarcinoma(0533b59c-e6ee-41fb-ad32-cb4784eadfa1).html.
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Pancreatic ductal adenocarcinoma (PDAC) is an aggressive form of cancer with poor prognosis and limited treatment options. Since many patients present with metastatic disease and are thus ineligible for surgical resection, PDAC is almost ubiquitously fatal; new treatment options are therefore needed to combat this disease. A key hallmark of many cancers, including PDAC, is metabolic reprogramming and a shift towards a high glycolytic rate, known as the Warburg effect. This allows cancer cells to generate ATP in the face of hypoxia and to meet the increased metabolic requirements associated with rapid proliferation. We hypothesised that this shift towards glycolytic metabolism has important implications for the regulation of cytosolic Ca2+ ([Ca2+]i) in PDAC, since the plasma membrane Ca2+ ATPase (PMCA), which is critical for maintaining low [Ca2+]i and thus cell survival, is dependent on ATP to extrude cytosolic Ca2+. The relative contributions of mitochondrial vs glycolytic ATP in fuelling the PMCA in human PDAC cell lines (PANC-1 and MIA PaCa-2) were therefore assessed. Moreover, the effects of numerous mechanistically distinct metabolic inhibitors on key readouts of cell death, [Ca2+]i and ATP were investigated. Treatment with glycolytic inhibitors induced significant ATP depletion, PMCA inhibition, [Ca2+]i overload and cell death in both PANC-1 and MIA PaCa-2 cells, while mitochondrial inhibitors had no effect. Subsequently, these experiments were repeated on PDAC cells cultured in media formulated to "switch" their highly glycolytic phenotype back to one more reliant on mitochondrial metabolism. Culture in nominal glucose-free media supplemented with either galactose (10 mM) or alpha-ketoisocaproate (KIC, 2 mM) resulted in a switch in metabolism in MIA PaCa-2 cells, where proliferation rate and glycolysis were significantly decreased, and in the case of cells cultured in KIC, oxidative phosphorylation rate was preserved (assessed using Seahorse XF technology). Following culture of MIA PaCa-2 cells in either galactose or KIC, glycolytic inhibition failed to recapitulate the profound ATP depletion, PMCA inhibition and [Ca2+]i overload observed in glucose-cultured MIA PaCa-2 cells. These data demonstrate that in PDAC cells exhibiting a high rate of glycolysis, glycolytically-derived ATP is important for fuelling [Ca2+]i homeostasis and thus is critical for survival. Finally, using a cell surface biotinylation assay, the keyglycolytic enzymes LDHA, PFKP, GAPDH, PFKFB3 and PKM2 were all found to associate with the plasma membrane in MIA PaCa-2 cells, possibly in a tyrosine phosphorylation-dependent manner. To investigate whether the dynamic membrane-association of glycolytic enzymes provides a privileged supply of ATP to the PMCA in PDAC, the effects of tyrosine kinase inhibitors was assessed on PMCA activity. However, while these inhibited PMCA activity, this occurred without accompanying global ATP depletion. These data indicate that glycolytic ATP is critical for the regulation of [Ca2+]i by the PMCA in PDAC, and that the glycolytic regulation of the PMCA may be an important therapeutic locus. However, further research is required to determine whether membrane-bound glycolytic enzymes regulate its activity.
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Moore, Jocelyn. "Post-transcriptional control of Drosophila pole plasm component, germ cell-less." Thesis, McGill University, 2008. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=115700.
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Mechanisms of post-transcriptional control are critical to deploy RNAs and proteins asymmetrically to a discrete region of cytoplasm at the posterior of the Drosophila oocyte and embryo, called the pole plasm and thus allow differentiation of the germline. Research presented in this thesis investigates the post-transcriptional control of Drosophila pole plasm component germ cell-less (gcl ). Maternal gcl activity is required for germ cell specification and gcl RNA and protein accumulate asymmetrically in the pole plasm. gcl RNA, but not Gcl protein, is also detected in somatic regions of the embryo, and ectopic expression of Gcl in the soma causes repression of somatic patterning genes suggesting that gcl RNA is subject to translational control. I find that Gcl is expressed during oogenesis, where its expression is regulated by translational repressor Bruno (Bru). Increased levels of Gcl are observed in the oocyte when Bru is reduced (i.e., in an arrest heterozygote) and Bru overexpression reduces the amount of Gcl. Consistent with this, reduction of the maternal dosage of Bru leads to ectopic Gcl expression in the embryo, which, in turn, causes repression of anterior huckebein RNA expression. Bruno binds directly to the gcl3'UTR in vitro, but surprisingly, this binding is largely independent of a Bruno Response Element (BRE) in the gcl 3'UTR and depends upon a novel site. Furthermore, the gcl BRE-like region is not required to repress Gcl expression during oogenesis or embryogenesis. I concluded that Bru regulates gcl translation in a BRE-independent manner. In addition, I established the role of the gcl 3'UTR in gcl RNA localization and translation using transgenes that replace the endogenous 3'UTR with the alpha-tubulin 3'UTR or place it in tandem to the bicoid 3'UTR. I find that accumulation of gcl RNA in the embryonic pole plasm requires the gcl 3'UTR. Moreover, Gel is restricted to the pole plasm by translational repression mediated by the gcl 3'UTR and a limiting pool of trans-acting translational repressors. The phenotypic consequences of loss of this translational control are relatively mild, suggesting that gcl translation does not require stringent repression in the soma.
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Jones, Andrea Kathryn. "The role of cyclic AMP in the regulation of cholesterol metabolism in human monocytes/macrophage cell lines." Thesis, Royal Veterinary College (University of London), 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.522614.
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De, Lira Maria Nathalia [Verfasser], and Elita [Gutachter] Avota. "The regulation of T cell metabolism by neutral sphingomyelinase 2 / Maria Nathalia De Lira ; Gutachter: Elita Avota." Würzburg : Universität Würzburg, 2020. http://d-nb.info/1221963252/34.
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Chantarasinlapin, Praew. "Regulation of Adipocyte Differentiation and Metabolism: Rab5-Guanine Nucleotide Exchange Factors and Methylglyoxal." FIU Digital Commons, 2017. http://digitalcommons.fiu.edu/etd/3227.
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Internalization and trafficking of ligand-receptor complex rely on a particular set of proteins, e.g. small GTPase protein Rab5 and its activators called guanine nucleotide exchange factors. Rab5-activating protein 6 (RAP6), a Vps9-containing protein, may participate in Rab5-mediated insulin signaling and receptor trafficking. A dicarbonyl compound methylglyoxal was found to alter insulin signaling in preadipocytes. This dissertation aimed to investigate the association of RAP6 activity on 3T3-L1 preadipocyte differentiation and those driven by methylglyoxal. Overexpression of RAP6 inhibited preadipocyte differentiation, Ser473-phosphorylation of Akt1, and expression of adipogenic marker PPARγ, but not C/EBPα. Methylglyoxal (10 µM) increased preadipocyte differentiation, proliferation and expression of PPARγ, C/EBPα and p-Akt1-Ser473, but appeared to be neutralized by RAP6 overexpression. The findings suggest that RAP6 may be a key modulator in regulating the stimulatory effect of methylglyoxal on preadipocyte differentiation. The associations of predominant methylglyoxal-derived adduct, methylglyoxal hydroimidazolone 1 (MGH1), with selected risk factors of chronic diseases in Black participants with and without type 2 diabetes (n=234 controls and n=254 cases) were also investigated. Only in individuals with diabetes, MGH1 levels were positively associated with fasting plasma glucose (B=0.240, p=0.037), homocysteine (B=0.355, p=0.014) and triglyceride (B=0.190, p=0.049). Being African Americans with type 2 diabetes was associated with lower MGH1 levels as compared to being Haitian American with diabetes (B=-0.334, p=0.016). The findings suggest that methylglyoxal may be linked to hyperglycemia and metabolic changes in type 2 diabetes, and may differently impact the development of diabetes across Black subgroups.
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DeMille, Desiree. "Identifying and Characterizing Yeast PAS Kinase 1 Substrates Reveals Regulation of Mitochondrial and Cell Growth Pathways." BYU ScholarsArchive, 2015. https://scholarsarchive.byu.edu/etd/5930.
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Glucose allocation is an important cellular process that is misregulated in the interrelated diseases obesity, diabetes and cancer. Cells have evolved critical mechanisms for regulating glucose allocation, one of which is sensory protein kinases. PAS kinase is a key sensory protein kinase that regulates glucose allocation in yeast, mice and man; and is a novel therapeutic target for the treatment of metabolic diseases such as obesity, diabetes and cancer. Despite its importance, the molecular mechanisms of PAS kinase function are largely unknown. Through large-scale protein-interaction studies, we have identified 93 novel binding partners for PAS kinase which help to expand its role in glucose allocation as well as suggest novel roles for PAS kinase including mitochondrial metabolism, cell growth/division, protein modification, stress tolerance, and gene/protein expression. From a subset of these binding partners, we identified 5 in vitro substrates of PAS kinase namely Mot3, Utr1, Zds1, Cbf1 and Pbp1. Additionally, we have further characterized Pbp1 and Cbf1 as PAS kinase substrates through both in vitro and in vivo evidence as well as phenotypic analysis. Evidence is provided for the PAS kinase-dependent phosphorylation and activation of Pbp1, which in turn inhibits cell proliferation through the sequestration of TORC1. In contract, PAS kinase-dependent phosphorylation of Cbf1 inhibits its activity, decreasing cellular respiration. This work elucidates novel molecular mechanisms behind PAS kinase function in both mitochondrial and cell growth pathways in eukaryotic cells, increasing our understanding of the regulation of central metabolism.
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Freitas, Claudia Mercedes. "Regulation of Immune Cell Activation and Functionby the nBMPp2 Protein andthe CD5 Co-Receptor." BYU ScholarsArchive, 2019. https://scholarsarchive.byu.edu/etd/8257.
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According to the centers for disease control and prevention (CDC) and the world healthorganization (WHO), heart disease and immune related diseases such as diabetes and cancer areamong the leading causes of death around the world. Thus, the regulation of the function ofimmune cell plays a key role in health and disease. Calcium (Ca2+) ions play a critical role inimmune cell activation, function and in a robust immune response. Defects in Ca2+ signalinginfluences the development of cardiac disease, Alzheimer disease, immune cell metabolism,muscle dysfunction, and cancer. Each immune cell is unique in its activation and function,making it relevant to understand how activation of each type of immune cell is regulated. Herewe describe the role of the nBMP2 protein in macrophage activation and function and the role ofthe CD5 co-receptor in helper T cell activation and function.The nuclear bone morphogenetic protein 2 (nBMP2) is the nuclear variant of the bonemorphogenetic protein 2 (BMP2), a growth factor important in heart development, neurogenesis,bone, cartilage and muscle development. To better understand the function of nBMP2, transgenicnBMP2 mutant mice were generated. These mice have a slow muscle relaxation and cognitivedeficit caused in part by abnormal Ca2+ mobilization. Mutant nBMP2 mice also have an impairedsecondary immune response to systemic bacterial challenge. Here we have further characterizedmacrophage activation and function from mutant nBMP2 mice before and after bacterialinfection. We describe how nBMP2 influences the Ca2+ mobilization response and phagocytosisin macrophages, revealing a novel role of the nBMP2 protein in immune cell regulation.CD5 is a surface marker on T cells, thymocytes, and the B1 subset of B cells. CD5 isknown to play an important role during thymic development of T cells. CD5 functions as anegative regulator of T cell receptor (TCR) signaling and fine tunes the TCR signaling response.Here we describe our characterization of CD5 regulation of Ca2+ signaling in naïve helper Tcells. We also outline our findings examining how CD5-induced changes in helper T cellactivation influence other biological processes such as immune cell metabolism, the diversity ofthe gut microbiome, and cognitive function and behavior. Thus, this work elucidates theinfluence of the CD5 co-receptor on the functional outcomes in multiple systems when CD5 isaltered.
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Häkkinen, Suvi T. "A functional genomics approach to the study of alkaloid biosynthesis and metabolism in Nicotiana tabacum and Hyoscyamus muticus cell cultures /." [Espoo, Finland] : VTT, 2008. http://www.vtt.fi/inf/pdf/publications/2008/P696.pdf.
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Vondracek, Martin. "Toxicity of smokeless tobacco in human oral epithelium with emphasis on carcinogen metabolism and regulation of programmed cell death /." Stockholm, 2002. http://diss.kib.ki.se/2002/91-7349-335-X/.
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Zhang, Wei. "Neurological - Molecular Interface in Food Intake and Metabolism in Birds and Mammals." Diss., Virginia Tech, 2014. http://hdl.handle.net/10919/64416.
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Obesity is a physiological consequence of dysregulated energy homeostasis. Energy homeostasis depends on energy intake and energy expenditure. Factors controlling the development of different adipose tissue deposits in the body and their distinct metabolic phenotypes are of considerable interest from both an agricultural and biomedical perspective. Following the literature review, the first chapter was devoted to studies designed to bridge the neural-adipose interface in understanding the relationship between appetite regulation and adipose tissue deposition in chickens, using chickens selected for low or high juvenile body weight as a model. Appetite regulation in the brain, particularly the hypothalamus, is the main factor governing food intake. Neuropeptide Y (NPY), known as a potent orexigenic factor, also promotes energy storage in fat in mammals and thus has a dual role in promoting energy intake via appetite regulation in the brain and energy storage/expenditure via direct effects on adipose tissue function. There have been no reports of the effects of NPY on adipose tissue function in any avian species. By exposing chicken preadipocytes to different concentration of NPY, we found that NPY enhances both proliferation and differentiation and thus appears to play a major role in chicken adipogenesis, an effect that has not yet been reported, to our knowledge. In the body weight selected chicken lines, we found that NPY and receptor sub-type expression was elevated in the abdominal fat of chickens from the high body weight chicken line and expression of these genes displayed heterosis in the reciprocal crosses of the parental lines as compared to both the high and low body weight selected lines. Intriguingly, expression of those same genes was greater in the low weight than high weight chickens in the hypothalamus. Hypothalamic transcriptomic profiling revealed that genes involved in serotonergic and dopaminergic systems may also play an important role in both appetite regulation and insulin-regulated energy homeostasis in the body weight chicken lines. Intracerebroventricular injection of serotonin in broiler chicks was associated with a dose and time dependent reduction in food intake that was coupled with the activation of the ventromedial hypothalamus and arcuate nucleus, as determined by c-fos immunoreactivity. The remainder of this dissertation project describes the effects of knocking down expression of a recently discovered transcription factor, ZBED6, on mouse preadipocyte proliferation and differentiation. The dissertation ends with a study using diet-induced porcine prepubertal obesity as a model to examine differences in adipokine gene expression between different fat depots from pigs that consumed diets that differed in carbohydrate composition. Overall, we conclude that both NPY and monoamines such as serotonin and dopamine are of importance in the regulation of energy balance in chickens. Moreover, we propose that NPY is a factor that mediates hypothalamus and adipose tissue crosstalk in chickens. An understanding of this system may provide a new avenue for the treatment of obesity and associated disease complications by re-orchestrating the neuronal outputs or adiposity inputs. This information may also be of value in developing strategies to improve feed conversion and meat yield in commercial broilers.<br>Ph. D.
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Pan, Tien-Chien. "Metabolic, cardiac and ventilatory regulation in early larvae of the South African clawed frog, Xenopus laevis." Thesis, University of North Texas, 2009. https://digital.library.unt.edu/ark:/67531/metadc12175/.
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Early development of O2 chemoreception and hypoxic responses under normoxic (150 mmHg) and chronically hypoxic (110 mmHg) conditions were investigated in Xenopus laevis from hatching to 3 weeks post fertilization. Development, growth, O2 consumption, ventilatory and cardiac performance, and branchial neuroepithelial cells (NEC) density and size were determined. At 3 days post fertilization (dpf), larvae started gill ventilation at a rate of 28 ± 4 beats/min and showed increased frequency to 60 ± 2 beats/min at a PO2 of 30 mmHg. Also at 3 dpf, NECs were identified in the gill filament buds using immunohistochemical methods. Lung ventilation began at 5 dpf and exhibited a 3-fold increase in frequency from normoxia to a PO2 of 30 mmHg. Hypoxic tachycardia developed at 5 dpf, causing an increase of 20 beats/min in heart rate, which led to a 2-fold increase in mass-specific cardiac output at a PO2 of 70 mmHg. At 10 dpf, gill ventilatory sensitivity to hypoxia increased, which was associated with the increase in NEC density, from 15 ± 1 to 29 ± 2 cells/mm of filament at 5 and 10 dpf, respectively. Unlike the elevated rate, cardiac and ventilatory volumes were independent of acute hypoxia. Despite increased cardioventilatory frequency, larvae experienced an average of 80% depression in during acute hypoxia. Chronic hypoxia (PO2 of 110 mmHg) decreased mass-specific cardiac performance before 10 dpf. In older larvae (10 to 21 dpf), chronic hypoxia decreased acute branchial and pulmonary hypoxic hyperventilation and increased NEC size. Collectively, these data suggest that larvae exhibit strong O2-driven acute hypoxic responses post-hatching, yet are still O2 conformers. All acute hypoxic responses developed before 5 dpf, and then the effects of chronic hypoxia started to show between 7 and 21 dpf. Thus, the early formation of acute hypoxic responses is susceptible to the environment and can be shaped by the ambient PO2.
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Lekholm, Emilia. "Solute Carriers in Metabolism : Regulation of known and putative solute carriers in the central nervous system." Doctoral thesis, Uppsala universitet, Funktionell farmakologi, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-331328.
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Solute carriers (SLCs) are membrane-bound transporter proteins, important for nutrient, ion, drug and metabolite transport across membranes. A quarter of the human genome codes for membrane-bound proteins, and SLCs make up the largest group of transporter proteins. Due to their ability to transport a large repertoire of substances across, not just the plasma membrane, but also the membrane of internal organelles, they hold a key position in maintaining homeostasis affecting metabolic pathways. Unfortunately, some of the more than 400 identified SLCs are still not fully characterized, even though a quarter of these are associated with human disease. In addition, there are about 30 membrane-bound proteins with strong resemblance to SLCs, of which very little is known. The aim of this thesis is to characterize some of these putative SLCs, focusing on their localization and function in the central nervous system. Since many of the known SLCs play a vital part in metabolism and related pathways, the response to different nutritional conditions has been used as a key method. MFSD14A and MFSD14B, characterized in Paper I, are putative SLCs belonging to the Major Facilitator Superfamily (MFS) and found to be neuronal, differentially expressed in the mouse central nervous system and transiently upregulated in mouse embryonic cortex cultures due to amino acid deprivation. They were also altered in areas of the mouse brain after starvation as well as after high fat diet. In Paper II, the effect on gene regulation due to complete amino acid starvation was monitored in a mouse hypothalamic cell line and 47 different genes belonging to SLCs, or putative SLCs, were found to be affected. Of these, 15 genes belonged to already known amino acid transporters, whereas 32 were putative SLCs with no known function or SLCs not known to react to amino acids. The three SV2 proteins, SV2A, SV2B and SV2C, were studied in Paper III using human neuroblastoma cell lines. The high metabolic state of cancers often result in an upregulation and alteration of transporter proteins, and alterations of the SV2 proteins were found following different treatments performed in this study. Paper IV focused on putative SLCs of MFS type and their role in glucose metabolism. Mouse embryonic cortex cultures were subjected to glucose starvation and the gene expression of 19 putative transporters were analyzed. All but four of the putative transporters were affected either at 3h or 12h of glucose deprivation. In conclusion, several SLCs and putative SLCs studied in this thesis are strongly affected by alteration in metabolism, either due to amino acids or glucose or both. This makes the putative SLCs dynamic membrane-bound proteins, possibly transporters, highly affected by nutritional status and most likely regulated to maintain homeostasis.
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Sun, Zheng Ernsberger Paul. "Imidazoline receptors in insulin signaling and metabolic regulation molecular basis for l1-imidazoline binding and cell signaling and the mechanisms linking this signaling protein to regulation glucose metabolism." Saarbrücken VDM Verlag Dr. Müller, 2007. http://d-nb.info/988497085/04.
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Wang, Sih-han. "Regulation of mitochondrial fates and cellular metabolism via parkin-mediated mitophagy and interaction between apoptosis and autophagy pathways in cancer." Diss., University of Iowa, 2012. https://ir.uiowa.edu/etd/3400.
Full textAbstract:
Apoptosis is a cell death pathway that regulates tissue homeostasis, and is often altered in oncogenesis. Autophagy is a lysosome degradation pathway that mediates cellular adaptation in response to stresses. Altered autophagy pathways are proposed to be associated with pathogenesis of neurodegenerative diseases and oncogenesis. The goal of this work is to study the complex link between apoptosis and autophagy pathways, and their possible roles in the development of cancer. Using transgenic mice models, we found that impaired apoptosis by overexpression of a dominant negative form of Caspase-9 (Casp9DN) failed to accelerate T-cell lymphoma either by itself or in tumor-prone Bax overexpressing transgenic mice. Additionally, heterozygous disruption of Beclin 1, a central upstream autophagy regulator, failed to promote T-cell lymphoma in either Casp9DN or tumor-prone Bax overexpressing transgenic mice. However, caspase inhibition enhanced a unique form of selective mitochondrial autophagy, referred to as mitochondrial outer membrane permeabilization (MOMP)-induced mitophagy. Parkin, a protein mutated in early-onset Parkinson's disease, mediates mitophagy following protonophore (CCCP) treatment, suggesting that Parkin may also play a role in MOMP-induced mitophagy. Thus, two different types of mitochondrial stresses, MOMP and CCCP, cause mitochondrial depolarization and induce mitophagy. We therefore examined if there is a mechanistic link between two mitophagy pathways. Focusing on the roles of autophagy and apoptosis regulators using isogenic hematopoietic cell lines, our studies demonstrate that MOMP-induced mitophagy is dependent upon Bcl-2 family members, but independent of Parkin or ULK1 (an autophagy regulator). In contrast, CCCP-induced mitophagy is dependent upon Parkin and ULK1, but independent of Bcl-2 family members. However, we found that both pathways ultimately result in the following properties: reduced mitochondrial respiration rate, altered cellular metabolism, and high sensitivity to 2-DG (an inhibitor of glycolysis). Interestingly, 2-DG induced cell death in cells following Parkin-dependent mitophagy is independent of Bcl-2 and Bax/Bak. Overall, the work in this dissertation demonstrates that the two different mitochondrial stresses, MOMP and protonophore (CCCP) treatment, lead to two mechanistically distinct mitophagy pathways, but both alter mitochondrial respiration and cellular metabolism.
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Simon, Molas Helga. "Exploring the regulation and function of TIGAR in cancer cells." Doctoral thesis, Universitat de Barcelona, 2019. http://hdl.handle.net/10803/667414.
Full textAbstract:
The TP53-Induced Glycolysis and Apoptosis Regulator (TIGAR) gene was described in 2006 by Dr. Karen Vousden's group in response to the induction of the tumour suppressor gene p53. Since then, numerous studies have focused on clarifying the role of this gene in the metabolism of tumour cells.
TIGAR was initially described as an enzyme with bisphosphatase activity on fructose-2,6-bisphosphate, a key metabolite in the positive allosteric regulation of phosphofructokinase-1, which catalyses a key reaction in glycolysis. Through this bisphosphatase activity, TIGAR reduces the levels of fructose-2,6-bisphosphate and, consequently, decreases the glycolytic flux and redirects the metabolites to the pentose phosphate pathway, which is determinant for the antioxidant capacity of cells. Overexpression of TIGAR has been described in multiple tumours, as well as in different cell lines, indicating that this gene confers a growth advantage to these cells.
The present doctoral thesis has focused on studying the metabolic function of TIGAR in tumours, as well as the mechanisms that regulate its transcription. The study was carried out on cell lines of cervical cancer and lung cancer in which we have been able to confirm that TIGAR exerts a bisphosphatase function on fructose-2,6-bisphosphate. TIGAR has proven to be key in the response of the cervical cancer cell line HeLa to the blockage of glycolysis, either by inhibiting the expression of the PFKFB3 gene by interfering RNA technology, or by blocking the PFK-2 protein by the drug 3PO. The blockage of glycolysis increases oxidative stress and the phosphorylation of the kinase Akt, which is required for the induction of TIGAR.
Furthermore, through metabolomic studies we have been able to describe for the first time the involvement of TIGAR in the entrance of pyruvate to the tricarboxylic acid cycle, in the mitochondria.
Finally, and in relation to the mechanisms that regulate the transcription of TIGAR, we have proved that the transcription factor Nrf2, key in the regulation of the antioxidant activity of tumour cells, controls the expression of TIGAR in HeLa cells. In lung cancer cells, where the over activation of Nrf2 is related to chemo resistance and radiotherapy, the relationship between Nrf2 and TIGAR seems to be indirect.
With the results presented in this doctoral thesis we have contributed to a better understanding of the role of TIGAR in tumour metabolism and have laid the foundations for future studies aimed at blocking this protein in tumours.<br>El gen TP53-Induced Glycolysis and Apoptosi Regulator (TIGAR) va ser descrit l'any 2006 pel grup de la Dra. Karen Vousden en resposta a l’activació del supressor tumoral p53. Des de llavors, nombrosos estudis s'han centrat en aclarir el paper d'aquest gen en el metabolisme de les cèl·lules tumorals. Inicialment, la funció atribuïda a TIGAR va ser la de bisfosfatasa de la fructosa-2,6-bisfosfat, metabòlit clau en la regulació al·lostèrica positiva de l’enzim fosfofructoquinasa-1, que catalitza la una reacció clau en la glucòlisi. Mitjançant aquesta activitat bisfosfatasa, TIGAR redueix els nivells de fructosa-2,6-bisfosfat i, en conseqüència, frena en flux glicolític i redirigeix els metabòlits a la via de les pentoses fosfat. És per aquest motiu que TIGAR es va descriure com un gen amb capacitat antioxidant.
La present tesi doctoral s'ha centrat en estudiar la funció metabòlica de TIGAR en línies tumorals, així com els mecanismes que regulen la seva transcripció. Amb aquests estudis hem pogut demostrar que TIGAR és clar en la resposta de les cèl·lules al bloqueig de la glucòlisi, ja sigui per la inhibició de l'expressió del gen PFKFB3 mitjançant la tecnologia de RNA d'interferència, com pel bloqueig de la proteïna PFK-2 mitjançant el fàrmac 3PO. El bloqueig de la glucòlisi provoca un augment de l'estrès oxidatiu i de la fosforil·lació de la quinasa Akt, necessària per a la inducció de TIGAR.que al seu torn condueix a una inducció de TIGAR.
D’altra banda, estudis metabolòmics ens han permès descriure per primera vegada l’acció de TIGAR en nivells inferiors de la glicòlisi, afectant l’entrada del piruvat al cicle de Krebs.
Finalment, hem pogut comprovar que el factor de transcripció Nrf2, clau en la regulació de l'activitat antioxidant de les cèl·lules, controla l'expressió de TIGAR en una línia cel·lular de càncer de cèrvix. En cèl·lules de càncer de pulmó, en canvi, la relació entre Nrf2 i TIGAR sembla ser indirecta.
Amb els resultats presentats en aquesta tesi doctoral hem contribuït a entendre millor el paper de TIGAR en el metabolisme tumoral i hem establert les bases per a futurs estudis dirigits al bloqueig d'aquesta proteïna als tumors.
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Niklas, Jens [Verfasser], and Elmar [Akademischer Betreuer] Heinzle. "Primary metabolism and its regulation in the human cell line AGE1.HN – application of metabolic flux analysis for improved biopharmaceutical production / Jens Niklas. Betreuer: Elmar Heinzle." Saarbrücken : Saarländische Universitäts- und Landesbibliothek, 2012. http://d-nb.info/1052339573/34.
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Gaul, Susanne [Verfasser], Annette G. [Akademischer Betreuer] Beck-Sickinger, Annette G. [Gutachter] Beck-Sickinger, and Wieland [Gutachter] Kiess. "The NAMPT-mediated NAD salvage pathway in cancer cell metabolism and its regulation by resveratrol / Susanne Schuster ; Gutachter: Annette G. Beck-Sickinger, Wieland Kiess ; Betreuer: Annette G. Beck-Sickinger." Leipzig : Universitätsbibliothek Leipzig, 2015. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-173401.
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Schuster, Susanne [Verfasser], Annette G. [Akademischer Betreuer] Beck-Sickinger, Annette G. [Gutachter] Beck-Sickinger, and Wieland [Gutachter] Kiess. "The NAMPT-mediated NAD salvage pathway in cancer cell metabolism and its regulation by resveratrol / Susanne Schuster ; Gutachter: Annette G. Beck-Sickinger, Wieland Kiess ; Betreuer: Annette G. Beck-Sickinger." Leipzig : Universitätsbibliothek Leipzig, 2015. http://d-nb.info/1239567219/34.
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