Mouse Models of Insulin Resistance

胰岛素抵抗小鼠模型

• 批准号: 10617186
• 负责人: DOMENICO ACCILI
• 金额: $ 49万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10617186
• 关键词: ADD-1 protein; Action Research; Address; Admixture; Affect; Affinity Chromatography; Alleles; Animal Experiments; Applied Genetics; Architecture; Automobile Driving; Award; Binding; Biochemical; Biology; Cells; Central Nervous System; Clinical; Complex; Cues; DNA; Data; Deposition; Diabetes Mellitus; Diet; Enteroendocrine Cell; Equilibrium; FOXO1A gene; FRAP1 gene; Family; Foundations; Gene Expression; Genes; Genetic; Genetic Epistasis; Genetic Techniques; Genetic Transcription; Gluconeogenesis; Glucose; Glycolysis; Goals; Grant; Hepatic; Hepatocyte; Hormone Responsive; Hormones; Human; Hypoglycemic Agents; Hypothalamic structure; Insulin; Insulin Resistance; Insulin Signaling Pathway; Intervention; Knowledge; Lipids; Liver; Maps; Mass Spectrum Analysis; Mediating; Medical; Metabolic; Metabolism; Metformin; Mind; Modality; Modeling; Molecular; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Translocation; Organoids; Orphan; Output; Pharmacopoeias; Phenotype; Phosphorylation; Physiological; Plasma; Production; Property; Proteins; Public Health; Research; Role; Satiation; Series; Signal Pathway; Signal Transduction; Site; Specificity; Syndrome; Testing; Therapeutic Effect; Tissues; Transcriptional Regulation; Translating; Triglycerides; cell type; db/db mouse; diabetes pathogenesis; diabetic; energy balance; experimental study; fatty acid oxidation; gene function; genetic corepressor; glucose production; glucose tolerance; improved; in vivo; inhibitor; innovation; insulin mediators; insulin regulation; insulin sensitivity; insulin sensitizing drugs; insulin signaling; knock-down; lipid biosynthesis; loss of function; member; mouse model; mutant; novel therapeutic intervention; pharmacologic; prevent; receptor; tissue mapping; transcription factor

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

Analysis of compensatory beta-cell response in mice with combined mutations of Insr and Irs2.

Insr 和 Irs2 联合突变小鼠的代偿性 β 细胞反应分析。

• DOI: 10.1152/ajpendo.00430.2006
• 发表时间: 2007
• 期刊: American journal of physiology. Endocrinology and metabolism
• 作者: Kim,JaneJ;Kido,Yoshiaki;Scherer,PhilippE;White,MorrisF;Accili,Domenico
• 通讯作者: Accili,Domenico

Mosaic analysis of insulin receptor function.

胰岛素受体功能的镶嵌分析。

• DOI: 10.1172/jci17810
• 发表时间: 2004
• 期刊: The Journal of clinical investigation
• 作者: Kitamura,Tadahiro;Kitamura,Yukari;Nakae,Jun;Giordano,Antonio;Cinti,Saverio;Kahn,CRonald;Efstratiadis,Argiris;Accili,Domenico
• 通讯作者: Accili,Domenico

FOXO1 inhibition yields functional insulin-producing cells in human gut organoid cultures.

• DOI: 10.1038/ncomms5242
• 发表时间: 2014-06-30
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Bouchi, Ryotaro;Foo, Kylie S.;Hua, Haiqing;Tsuchiya, Kyoichiro;Ohmura, Yoshiaki;Sandoval, P. Rodrigo;Ratner, Lloyd E.;Egli, Dieter;Leibel, Rudolph L.;Accili, Domenico
• 通讯作者: Accili, Domenico