V-ATPase H+ PUMP REGULATION IN FUEL ENERGY SELECTION
燃料能量选择中的 V-ATPase H 泵调节
基本信息
- 批准号:8475614
- 负责人:
- 金额:$ 28.56万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-08-01 至 2015-11-30
- 项目状态:已结题
- 来源:
- 关键词:Acetyl Coenzyme AAcid-Base EquilibriumAddressAfrican AmericanAlaska NativeAldehyde-LyasesAmerican IndiansBacterial ToxinsBindingBiochemicalBiological ModelsCarbonCell membraneCellsChronic Kidney FailureCitratesComplementComplexCoupledCouplesDefectDevelopmentDiabetes MellitusDiseaseElementsEndosomesEnergy MetabolismEnzymesEthnic groupFatty AcidsFatty acid glycerol estersFructoseFunctional disorderGeneticGlucoseGlycolysisGoalsHealthHispanicsIn VitroInsulin ResistanceIntercalated CellKidneyKidney DiseasesKnowledgeLinkLysosomesMacromolecular ComplexesMalignant NeoplasmsMalonyl Coenzyme AMeasuresMembraneMetabolicMetabolic ControlMetabolic DiseasesMetabolismModelingMolecularMolecular StructureNephronsNutrientObesityOrganismPathway interactionsPhysiologyProcess MeasureProteinsProton PumpProtonsPublic HealthPumpQuality of lifeRaceRegulationResearchRisk FactorsSaccharomyces cerevisiaeSignal TransductionSorting - Cell MovementSourceStructureSystemTestingVacuoleVirusWarburg EffectYeast Model SystemYeastscancer cellextracellularfatty acid metabolismfatty acid oxidationglucose metabolismin vivoinsightinterestkidney celllipid metabolismlysosome membranemetabolic abnormality assessmentmutantnoveloxidationpH Homeostasisreconstitutionresponsevacuolar H+-ATPase
项目摘要
DESCRIPTION (provided by applicant): V-ATPases are conserved proton pumps important to pH homeostasis. Located at the membrane of lysosomes, vacuoles and endosomes, V-ATPases sustain the acidic luminal pH needed for protein sorting and degradation; and for entry of viruses and bacterial toxins into host cells. Cells specialized for active proton secretion such as the 1-intercalated cells of the kidney nephron, express V-ATPases at the plasma membrane where they fine-tune the systemic acid-base balance. It is our goal to demonstrate the fundamental mechanisms that carefully regulate V-ATPase function and assembly in order to gain insight into how V- ATPases assist in controlling luminal, cytosolic, and extracellular pH. V-ATPases are dynamic structures that reversibly disassemble to control pH. In yeast and kidney cells, activity and V-ATPase assembly are coupled with glycolysis, but the mechanisms involved are unclear. Using yeast model systems, we have shown a novel link between V-ATPases and the glucose-fatty acid cycle, suggesting that glucose and lipid metabolism remodel pH homeostasis via effects on V-ATPases. It is our hypothesis that V-ATPase assembly is regulated as a means of maintaining cellular pH homeostasis when metabolism switches between glucose and fatty acids. We propose that a complex consisting of the V-ATPase pump and glycolytic enzymes functionally and structurally couples pH homeostasis and energy metabolism; and that metabolic control of this macromolecular structure regulates V-ATPase assembly. Three specific aims will test this model: Aim 1 will dissect the metabolic signals that link V-ATPase to the glycolytic pathway; Aim 2 will elucidate the mechanisms by which regulation of glycolytic enzymes remodels V-ATPase assembly and activity; and Aim 3 will establish how activation of the glucose-fatty acid cycle cross-talks to V-ATPases. In order to accomplish the aims proposed, this study will measure V-ATPase assembly and disassembly in vma mutants and metabolic mutants deficient in key steps of glycolysis, 2- oxidation of fatty acids, and the glucose-fatty acid cycle. Parallels will be established between intracellular levels of metabolic intermediates and dynamics of binding between V-ATPase and glycolytic enzymes enabling us to understand how V-ATPases assist cells in adjusting to metabolic changes. Because of the complexity involved in both comprehensive metabolic studies and regulation of V-ATPase pumps by reversible disassembly, S. cerevisiae is an outstanding system to address this mechanism at both the genetic and biochemical levels. By showing the contribution of V-ATPases, new insights into the mechanisms that tune fuel energy selection will emerge. Cancer cells use V-ATPases to regulate pH as a result of changes in metabolism; thus new knowledge on the mechanisms by which V-ATPases maintain pH homeostasis in cancer may be revealed. As pathophysiology of the glucose-fatty acid cycle results in metabolic disorders including diabetes and chronic kidney disease, our studies will also contribute towards their understanding.
描述(由申请人提供):v - atp酶是对pH稳态很重要的保守质子泵。v - atp酶位于溶酶体、液泡和核内体的膜上,维持蛋白质分选和降解所需的酸性腔内pH;以及病毒和细菌毒素进入宿主细胞。专门用于活跃质子分泌的细胞,如肾肾素的1插层细胞,在质膜上表达v - atp酶,在那里它们微调全身酸碱平衡。我们的目标是证明精心调节V- atp酶功能和组装的基本机制,以便深入了解V- atp酶如何协助控制腔内,胞质和细胞外ph。V- atp酶是可逆分解以控制ph的动态结构。在酵母和肾细胞中,活性和V- atp酶组装与糖酵解相结合,但所涉及的机制尚不清楚。利用酵母模型系统,我们发现了v - atp酶与葡萄糖-脂肪酸循环之间的新联系,表明葡萄糖和脂质代谢通过对v - atp酶的影响来重塑pH稳态。我们的假设是,当代谢在葡萄糖和脂肪酸之间转换时,v - atp酶组装作为维持细胞pH稳态的一种手段受到调节。我们认为一个由v - atp酶泵和糖酵解酶组成的复合物在功能和结构上耦合了pH稳态和能量代谢;这种大分子结构的代谢控制调节了v - atp酶的组装。三个特定的目标将测试该模型:目标1将剖析连接v - atp酶与糖酵解途径的代谢信号;目的2将阐明糖酵解酶调节v - atp酶组装和活性的机制;Aim 3将确定葡萄糖-脂肪酸循环的激活如何与v - atp酶交叉对话。为了实现上述目标,本研究将测量vma突变体和缺乏糖酵解、脂肪酸2-氧化和葡萄糖-脂肪酸循环关键步骤的代谢突变体中v - atp酶的组装和拆卸。将在细胞内代谢中间体水平和v - atp酶与糖酵解酶之间的结合动力学之间建立相似之处,使我们能够了解v - atp酶如何协助细胞适应代谢变化。由于综合代谢研究和v - atp酶泵可逆分解调控的复杂性,酿酒酵母在遗传和生化水平上都是解决这一机制的杰出系统。通过展示v - atp酶的作用,对调节燃料能量选择机制的新见解将会出现。癌细胞利用v - atp酶来调节pH值,这是新陈代谢变化的结果;从而揭示v - atp酶在癌症中维持pH稳态的机制。由于葡萄糖-脂肪酸循环的病理生理导致代谢紊乱,包括糖尿病和慢性肾脏疾病,我们的研究也将有助于他们的理解。
项目成果
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Advances in targeting the vacuolar proton-translocating ATPase (V-ATPase) for anti-fungal therapy.
- DOI:10.3389/fphar.2014.00004
- 发表时间:2014
- 期刊:
- 影响因子:5.6
- 作者:Hayek SR;Lee SA;Parra KJ
- 通讯作者:Parra KJ
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Karlett J Parra其他文献
Karlett J Parra的其他文献
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{{ truncateString('Karlett J Parra', 18)}}的其他基金
2013-2015 Bioenergetics Gordon Research Conference
2013-2015年生物能量学戈登研究会议
- 批准号:
8517951 - 财政年份:2013
- 资助金额:
$ 28.56万 - 项目类别:
Flow Cytometry HTS of Small Molecules that Regulate V-ATPase Proton Transport in
调节 V-ATP 酶质子转运的小分子的流式细胞术 HTS
- 批准号:
8069470 - 财政年份:2011
- 资助金额:
$ 28.56万 - 项目类别:
V-ATPASE PUMPS IN PROSTATE CANCER: REGULATORY AND FUNCTIONAL STUDIES
前列腺癌中的 V-ATP 酶泵:调节和功能研究
- 批准号:
8359765 - 财政年份:2011
- 资助金额:
$ 28.56万 - 项目类别:
Flow Cytometry HTS of Small Molecules that Regulate V-ATPase Proton Transport in
调节 V-ATP 酶质子转运的小分子的流式细胞术 HTS
- 批准号:
8210811 - 财政年份:2011
- 资助金额:
$ 28.56万 - 项目类别:
V-ATPASE PUMPS IN PROSTATE CANCER: REGULATORY AND FUNCTIONAL STUDIES
前列腺癌中的 V-ATP 酶泵:调节和功能研究
- 批准号:
8167588 - 财政年份:2010
- 资助金额:
$ 28.56万 - 项目类别:
V-ATPase H+ PUMP REGULATION IN FUEL ENERGY SELECTION
燃料能量选择中的 V-ATPase H 泵调节
- 批准号:
8129080 - 财政年份:2009
- 资助金额:
$ 28.56万 - 项目类别:
V-ATPase H+ PUMP REGULATION IN FUEL ENERGY SELECTION
燃料能量选择中的 V-ATPase H 泵调节
- 批准号:
8039389 - 财政年份:2009
- 资助金额:
$ 28.56万 - 项目类别:
V-ATPase H+ PUMP REGULATION IN FUEL ENERGY SELECTION
燃料能量选择中的 V-ATPase H 泵调节
- 批准号:
8078880 - 财政年份:2009
- 资助金额:
$ 28.56万 - 项目类别:
V-ATPase H+ PUMP REGULATION IN FUEL ENERGY SELECTION
燃料能量选择中的 V-ATPase H 泵调节
- 批准号:
8300360 - 财政年份:2009
- 资助金额:
$ 28.56万 - 项目类别:
V-ATPase H+ PUMP REGULATION IN FUEL ENERGY SELECTION
燃料能量选择中的 V-ATPase H 泵调节
- 批准号:
8013758 - 财政年份:2009
- 资助金额:
$ 28.56万 - 项目类别:
相似海外基金
Acid-base Equilibrium in Protic Ionic Liquids
质子离子液体中的酸碱平衡
- 批准号:
19750062 - 财政年份:2007
- 资助金额:
$ 28.56万 - 项目类别:
Grant-in-Aid for Young Scientists (B)














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