AS160 as a nodal regulator of the cardiac response to metabolic stress

AS160 作为心脏对代谢应激反应的节点调节剂

基本信息

  • 批准号:
    10518319
  • 负责人:
  • 金额:
    $ 56.32万
  • 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:
    2022-08-01 至 2027-07-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY Heart disease is the leading cause of death for both men and women in the United States. Cardiovascular mortality rates positively correlate with the presence of diabetes, obesity and metabolic syndrome, which are rising in epidemic proportions and leading to poor outcomes including heart failure. There is a consensus that abdominal obesity is a major driving force in the pathogenesis of metabolic syndrome, with severe adverse effects on cardiovascular risk factors. In the midst of a growing recognition of how adipose tissue dysfunction and adipokine imbalance affect cardiac disease in the obese population, a less-well understood mechanism is the effect of cardiac metabolism and function on systemic metabolic homeostasis. In fact, little is known about the factors that link cardiac dysfunction and systemic metabolism. I have a long-standing interest in translational cardiovascular research, with previous investigations showing that elevated GRK2 activity and expression occurs early in disease and contributes to progression. Recently, my lab has shown that cardiac restricted expression of a short, amino terminal fragment of GRK2 (βARKnt) is cardioprotective. Further, while GRK2 negatively affects insulin signaling through a direct interaction with and phosphorylation of insulin receptor substrate-1 (IRS1), βARKnt enhances activation of the insulin signaling pathway and mitochondrial efficiency. Our preliminary data also show that βARKnt reduces abdominal fat content and preserves systemic insulin responsiveness during high fat diet-induced obesity. Currently, we discovered selective interactions of endogenous GRK2 and βARKnt with Akt substrate of 160kDa (AS160). Pathway analysis of this proteomic data confirmed an AS160/GRK2 link and involved numerous regulators of insulin signaling. AS160 has been identified as nodal regulator between insulin signaling and glucose uptake, but research into its physiological role in cardiomyocyte metabolism has been hampered by limitations of available or selected models. We hypothesize that enhancing AS160 signaling in cardiomyocytes improves their metabolic flexibility in a cardioprotective manner and translates these to beneficial effects on systemic insulin responsiveness. Aim 1 will interrogate the physiological role of cardiac AS160 in insulin-stimulated GLUT4 membrane trafficking and the functional consequences for metabolite uptake and mitochondrial respiration in the heart. Aim 2 will elucidate the composition of the cardiac AS160 regulatory complex using cross-linking/mass spectrometry to visualize the components and their interactions in human left ventricular samples from patients with heart failure with or without diabetes compared to murine mimics of disease. These studies seek to fill important gaps in our knowledge regarding the composition of the cardiac AS160 regulatory complex, how it is altered during cardiometabolic stress, how it regulates cardiomyocyte metabolite utilization, and whether it translates this to influencing systemic metabolic performance. Our overall goal is to gain a better understanding of the regulation and relevance of AS160 in cardiomyocyte insulin- responsiveness and whether it represents a therapeutic target for cardiometabolic disease.
项目总结

项目成果

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Sarah Marie Bass其他文献

Sarah Marie Bass的其他文献

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{{ truncateString('Sarah Marie Bass', 18)}}的其他基金

AS160 as a nodal regulator of the cardiac response to metabolic stress
AS160 作为心脏对代谢应激反应的节点调节器
  • 批准号:
    10674917
  • 财政年份:
    2022
  • 资助金额:
    $ 56.32万
  • 项目类别:
Unique Domain Features of GRK2 and Roles in Cardiovascular Disease
GRK2 的独特结构域特征及其在心血管疾病中的作用
  • 批准号:
    9332419
  • 财政年份:
    2016
  • 资助金额:
    $ 56.32万
  • 项目类别:
Unique Domain Features of GRK2 and Roles in Cardiovascular Disease
GRK2 的独特结构域特征及其在心血管疾病中的作用
  • 批准号:
    9899299
  • 财政年份:
    2016
  • 资助金额:
    $ 56.32万
  • 项目类别:

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