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.

抽象的胰岛素抵抗是对全世界公共健康的重大威胁，也是一个很大程度上未得到满足的医疗问题需要。为了揭示这种千变万化的综合症的复杂生物学原理，我们努力应用遗传学方法探测与代谢相关的基因功能和组织相互作用的技术，并识别可处理的 2 型糖尿病药物干预的目标。优异奖颁发的十年间，这笔赠款对我们了解胰岛素抵抗综合征的显着贡献包括：(i) 绘制胰岛素抵抗对糖尿病发病和进展的组织特异性贡献； (ii) 中枢神经系统中不同细胞类型的鉴定和分子特征介导胰岛素和反调节激素对血糖水平、饱腹感、和能量平衡； (iii) Gpr17 的发现和分子表征，Gpr17 是一种孤儿受体，介导下丘脑胰岛素的厌食作用； (iv) 显着的表现肠内分泌细胞转化为葡萄糖反应性胰岛素生成细胞的特性在实验动物以及人类类器官培养物中。在此基础上，本次重点更新应用是为了了解调节肝脏的胰岛素信号通路的分歧葡萄糖和脂质的产生，同时突出 FoxO 独立的转录机制通过胰岛素调节。为此，PI 提供了初步数据，确定了一系列广泛的激素- 反应性肝转录因子，并概述了表征其对胰岛素贡献的两个目标反抗。目标 1 将深入研究转录因子 FoxK1 和 FoxK2 在介导葡萄糖产量增加和甘油三酯合成增加的矛盾混合物，其特点是糖尿病肝。具体来说，实验将测试 Akt 和 mTOR 的磷酸化是否存在差异这些蛋白质上的位点影响它们的转录输出。目标 2 将分析高水平的贡献迁移组转录因子 TOX4 参与糖异生和甘油三酯从头合成。在两者中目标，将利用现有胰岛素抵抗模型的广泛上位性来回答新发现的因素是否独立于已知的胰岛素还是与已知的胰岛素重叠的问题信号方式。拟议的工作将增进我们对胰岛素抵抗的理解在生化、遗传和综合生理水平上治疗综合征，最终目标是将新获得的信息转化为创新的治疗方法。