Beta cell Notch activity in Type 2 Diabetes

2 型糖尿病中的 Beta 细胞 Notch 活性

基本信息

  • 批准号:
    10592434
  • 负责人:
  • 金额:
    $ 56.53万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-04-01 至 2026-03-31
  • 项目状态:
    未结题

项目摘要

Project Abstract β cell mass and function adapts to the insulin requirements of the organism to maintain euglycemia across a wide range of pathophysiology, such as insulin resistance induced by obesity, pregnancy or aging. Although molecular mechanisms that enable β cell adaptation to these stressors are not yet fully understood, insufficient functional adaptation becomes clinically apparent with the onset of Type 2 Diabetes (T2D). With the continued increase in obesity, novel therapeutically-tractable pathways that regulate β cell adaptation are sought to reverse β cell dysfunction in T2D. Notch is a highly conserved family of proteins critical for cell fate decision-making; in the developing endocrine pancreas, Notch signaling regulates β cell differentiation, but less is known about Notch action in mature tissue. We have recently shown that Notch signaling is present at low levels in fully developed β cells, but increased in islets cultured in high glucose or isolated from obese mice. Persistent β cell Notch signaling appears detrimental to function, as we observed improved glucose tolerance with genetic inhibition of β cell Notch action. Conversely, forced Notch activation impaired glucose-stimulated insulin secretion (GSIS) in isolated mouse or human islets, and induced glucose intolerance in β cell-specific Notch gain-of-function mice. In Aim 1, we investigate mechanism of increased β cell Notch activity, leveraging data showing that β cell expression of the Notch ligand, Jagged1, tracks with Notch activity. We test whether β cell Jagged1 is necessary and sufficient for the maladaptive β cell Notch response in obesity. In Aim 2, we address mechanism of Notch-induced GSIS defects. In key preliminary data, we found that Notch induces degradation of MafA, a key regulator of β cell maturity disrupted in T2D. We also observe novel MafA acetylations, blocked by Notch activity. We now study whether MafA stability and activity is dependent on acetylations, and elucidate the molecular machinery underlying these post-translational modifications. We also test whether Notch impacts stability and acetylation of the closely related transcription factor, MafB. Finally, in Aim 3, we test implications of our identified NOTCH-MAFA/B axis in human β cell transcriptional and function response to glucose, as well as effects on β cell heterogeneity in human islets. Achieving the goals of this application will determine upstream signals for Notch activation, downstream effectors of Notch-induced β cell dysfunction, and potentially develop novel therapeutic directions for the care of patients with T2D.
项目摘要

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Utpal Pajvani其他文献

Utpal Pajvani的其他文献

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{{ truncateString('Utpal Pajvani', 18)}}的其他基金

Pilot and Feasibility Program
试点和可行性计划
  • 批准号:
    10612975
  • 财政年份:
    2022
  • 资助金额:
    $ 56.53万
  • 项目类别:
Adipsin in NASH
NASH 中的脂肪素
  • 批准号:
    10530839
  • 财政年份:
    2022
  • 资助金额:
    $ 56.53万
  • 项目类别:
Adipsin in NASH
NASH 中的脂肪素
  • 批准号:
    10636848
  • 财政年份:
    2022
  • 资助金额:
    $ 56.53万
  • 项目类别:
Jagged-Notch signaling in NASH/fibrosis
NASH/纤维化中的锯齿状Notch信号传导
  • 批准号:
    10744371
  • 财政年份:
    2019
  • 资助金额:
    $ 56.53万
  • 项目类别:
Jagged-Notch signaling in NASH/fibrosis
NASH/纤维化中的锯齿状Notch信号传导
  • 批准号:
    10338130
  • 财政年份:
    2019
  • 资助金额:
    $ 56.53万
  • 项目类别:
Notch, Type 2 Diabetes and NAFLD
Notch、2 型糖尿病和 NAFLD
  • 批准号:
    9981180
  • 财政年份:
    2015
  • 资助金额:
    $ 56.53万
  • 项目类别:
Notch, Type 2 Diabetes and NAFLD
Notch、2 型糖尿病和 NAFLD
  • 批准号:
    10379465
  • 财政年份:
    2015
  • 资助金额:
    $ 56.53万
  • 项目类别:
Notch, Type 2 Diabetes and NAFLD
Notch、2 型糖尿病和 NAFLD
  • 批准号:
    10597002
  • 财政年份:
    2015
  • 资助金额:
    $ 56.53万
  • 项目类别:
Notch, Type 2 Diabetes and NAFLD
Notch、2 型糖尿病和 NAFLD
  • 批准号:
    10162415
  • 财政年份:
    2015
  • 资助金额:
    $ 56.53万
  • 项目类别:
Notch, Type 2 Diabetes and NAFLD
Notch、2 型糖尿病和 NAFLD
  • 批准号:
    10557969
  • 财政年份:
    2015
  • 资助金额:
    $ 56.53万
  • 项目类别:

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