Mouse Models of Insulin Resistance

胰岛素抵抗小鼠模型

• 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
• 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

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 胰岛素抵抗是全世界公共卫生的重大威胁，并且在很大程度上未得到医学 需要。为了揭示该蛋白质综合征的复杂生物学，我们努力应用遗传 探测基因功能和与代谢相关的组织相互作用的技术，并鉴定可导致的 2型糖尿病的药理干预靶标。在绩效奖的十年中， 这笔赠款对我们对胰岛素抵抗综合征的了解的显着贡献包括：（i） 绘制胰岛素抵抗对糖尿病的发作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表征 介导胰岛素和反调节激素对等离子体葡萄糖水平，饱腹感的不同影响 和能量平衡； （iii）GPR17的发现和分子表征，一种孤儿受体 介导胰岛素在下丘脑中的厌食作用； （iv）杰出的演示 肠内分泌细胞的特性将转化为葡萄糖响应性胰岛素产生细胞 在实验动物以及人体器官培养中。在这个基础的基础上，重点 更新应用是要了解调节肝的胰岛素信号通路的差异 葡萄糖和脂质产生，同时使转录的前FOXO无关机制 胰岛素调节。为此，PI列出了初步数据，以识别一组广泛的激素 - 响应式肝转录因子，并概述了两个旨在表征其对胰岛素的贡献的目的 反抗。 AIM 1将深入研究转录因子FOXK1和FOXK2在中介中的作用 葡萄糖产生和甘油三酸酯合成增加的矛盾混合物的特征是 糖尿病肝。具体而言，实验将测试AKT和MTOR的差异化磷酸化是否差异化 这些蛋白质上的位点会影响其转录输出。 AIM 2将分析高位的贡献 迁移率组转录因子Tox4对糖异生和从头甘油三酸酯的合成。在这两个中 目的，将采用现有胰岛素抵抗模型的广泛上述性 新确定的因素是与已知胰岛素重叠或重叠的问题 信号传导方式。拟议的工作将提高我们对胰岛素耐药性的理解 生化，遗传和综合生理水平的综合征，其最终目标是 将新获得的信息转化为创新的治疗方法。