Mouse Models of Insulin Resistance
胰岛素抵抗小鼠模型
基本信息
- 批准号:10207591
- 负责人:
- 金额:$ 49万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-07-01 至 2024-04-30
- 项目状态:已结题
- 来源:
- 关键词:Action ResearchAddressAdmixtureAffectAffinity ChromatographyAllelesAnimalsArchitectureAutomobile DrivingAwardBindingBiochemicalBiochemical GeneticsBiologyCellsClinicalComplexCuesDNADataDepositionDiabetes MellitusDietEnteroendocrine CellEquilibriumFOXO1A geneFRAP1 geneFamilyFoundationsGene ExpressionGenesGeneticGenetic EpistasisGenetic TechniquesGenetic TranscriptionGluconeogenesisGlucoseGlycolysisGoalsGrantHepaticHepatocyteHormone ResponsiveHormonesHumanHypoglycemic AgentsHypothalamic structureInsulinInsulin ResistanceInsulin Signaling PathwayInterventionKnowledgeLightLipidsLiverMapsMass Spectrum AnalysisMediatingMedicalMetabolicMetabolismMetforminMindModalityModelingMolecularNeuraxisNon-Insulin-Dependent Diabetes MellitusNuclear TranslocationOrganoidsOrphanOutputPharmacologyPharmacopoeiasPhenotypePhosphorylationPhysiologicalPlasmaProductionPropertyProteinsPublic HealthResearchRoleSatiationSeriesSignal PathwaySignal TransductionSiteSpecificitySyndromeTestingTherapeutic EffectTissuesTranscriptional RegulationTranslatingTriglyceridescell typedb/db mousediabetes pathogenesisdiabeticenergy balanceexperimental studyfatty acid oxidationgene functiongenetic corepressorglucose productionglucose toleranceimprovedin vivoinhibitor/antagonistinnovationinsulin mediatorsinsulin regulationinsulin sensitivityinsulin sensitizing drugsinsulin signalingknock-downlipid biosynthesisloss of functionmembermouse modelmutantpreventreceptortranscription factor
项目摘要
ABSTRACT
Insulin resistance stands as a significant threat to public health worldwide, and a largely unmet medical
need. To unravel the complex biology of this protean syndrome, we endeavored to apply genetic
techniques to probe gene function and tissue interactions related to metabolism, and identify tractable
targets for pharmacological intervention in type 2 diabetes. Over the ten years of the MERIT award,
notable contributions of this grant to our knowledge of the insulin resistance syndrome have included: (i)
mapping the tissue-specific contributions of insulin resistance to the onset and progression of diabetes;
(ii) identification and molecular characterization of distinct cell types in the central nervous system that
mediate different effects of insulin and counterregulatory hormones on plasma glucose levels, satiety,
and energy balance; (iii) discovery and molecular characterization of Gpr17, an orphan receptor that
mediates the anorexigenic effects of insulin in the hypothalamus; (iv) demonstration of the remarkable
property of enteroendocrine cells to undergo conversion into glucose-responsive insulin-producing cells
in experimental animals as well as human organoid cultures. Building on this foundation, the focus of this
renewal application is to understand the divergence of insulin signaling pathways regulating hepatic
glucose and lipid production, while bringing to the fore FoxO-independent mechanisms of transcriptional
regulation by insulin. To that end, the PI presents preliminary data identifying a broad set of hormone-
responsive hepatic transcription factors, and outlines two aims to characterize their contribution to insulin
resistance. Aim 1 will delve into the role of transcription factors FoxK1 and FoxK2 in mediating the
paradoxical admixture of increased glucose production and triglyceride synthesis that characterizes the
diabetic liver. Specifically, experiments will test whether differential phosphorylation at Akt and mTOR
sites on these proteins affects their transcriptional output. Aim 2 will analyze the contribution of the high
mobility group transcription factor TOX4 to gluconeogenesis and de novo triglyceride synthesis. In both
aims, extensive epistasis with existing models of insulin resistance will be employed to answer the
question of whether the newly identified factors are independent of or overlapping with known insulin
signaling modalities. The proposed body of work will advance our understanding of the insulin-resistant
syndrome at the biochemical, genetic, and integrated physiological levels, with the ultimate goal of
translating newly acquired information into innovative approaches to treatment.
摘要
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(4)
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DOMENICO ACCILI其他文献
DOMENICO ACCILI的其他文献
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{{ truncateString('DOMENICO ACCILI', 18)}}的其他基金
Insulin Resistance in Vascular Endothelial Cells and Foxo
血管内皮细胞的胰岛素抵抗和 Foxo
- 批准号:
8460254 - 财政年份:2007
- 资助金额:
$ 49万 - 项目类别:
PPAR-gamma Deacetylation in Cardiometabolic Disease
心脏代谢疾病中的 PPAR-gamma 脱乙酰化
- 批准号:
10428379 - 财政年份:2007
- 资助金额:
$ 49万 - 项目类别:
PPAR-gamma Deacetylation in Cardiometabolic Disease
心脏代谢疾病中的 PPAR-gamma 脱乙酰化
- 批准号:
10197191 - 财政年份:2007
- 资助金额:
$ 49万 - 项目类别:
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