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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：
DOMENICO ACCILI
金额：
$ 49万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
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：
https://reporter.nih.gov/project-details/10207591
关键词：
Action Research Address Admixture Affect Affinity Chromatography Alleles Animals Architecture Automobile Driving Award Binding Biochemical Biochemical Genetics Biology Cells 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 Light Lipids Liver Maps Mass Spectrum Analysis Mediating Medical Metabolic Metabolism Metformin Mind Modality Modeling Molecular Neuraxis Non-Insulin-Dependent Diabetes Mellitus Nuclear Translocation Organoids Orphan Output Pharmacology 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/antagonist innovation insulin mediators insulin regulation insulin sensitivity insulin sensitizing drugs insulin signaling knock-down lipid biosynthesis loss of function member mouse model mutant prevent receptor transcription 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