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

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)
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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

Mouse Models of Insulin Resistance
胰岛素抵抗小鼠模型
  • 批准号:
    10617186
  • 财政年份:
    2020
  • 资助金额:
    $ 49万
  • 项目类别:
Mouse Models of Insulin Resistance
胰岛素抵抗小鼠模型
  • 批准号:
    10395560
  • 财政年份:
    2020
  • 资助金额:
    $ 49万
  • 项目类别:
Mouse Models of Insulin Resistance
胰岛素抵抗小鼠模型
  • 批准号:
    10057493
  • 财政年份:
    2020
  • 资助金额:
    $ 49万
  • 项目类别:
MOUSE MODELS OF INSULIN RESISTANCE
胰岛素抵抗的小鼠模型
  • 批准号:
    9045751
  • 财政年份:
    2015
  • 资助金额:
    $ 49万
  • 项目类别:
Diabetes and Endocrinology Research Center
糖尿病与内分泌研究中心
  • 批准号:
    8063347
  • 财政年份:
    2010
  • 资助金额:
    $ 49万
  • 项目类别:
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:
Islet and Immunology
胰岛和免疫学
  • 批准号:
    7500528
  • 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:
Admin Core
管理核心
  • 批准号:
    7509429
  • 财政年份:
    2007
  • 资助金额:
    $ 49万
  • 项目类别:

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