Follistatin regulation of energy and lipid metabolism during progression of atherosclerosis

卵泡抑素对动脉粥样硬化进展过程中能量和脂质代谢的调节

基本信息

  • 批准号:
    10412836
  • 负责人:
  • 金额:
    $ 14.88万
  • 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:
    2022-05-10 至 2026-03-31
  • 项目状态:
    未结题

项目摘要

Abstract Atherosclerosis is the underlying cause of great majority of cardiovascular diseases (CVD) and poses a great threat to public health. Activation of thermogenic adipocytes reduces cholesterol levels and protects against atherosclerosis in animal models. Lower thermogenic adipocyte activity in dyslipidemic patients has been characterized by high plasma triglycerides (TG), low plasma high density lipoprotein cholesterol (HDL-C) concentration and lower uncoupling protein 1 (UCP1) expression. These findings in mice and humans underscore the importance of inducers of the thermogenic adipocyte program as potential therapeutic targets for the treatment of dyslipidemia and CVD. Our published and preliminary data demonstrate that follistatin (Fst) plays an important role not only in adipocyte browning but also in lipoprotein metabolism to regulate TG, total cholesterol (TC), and HDL-C levels. In this proposal, we will test our central hypothesis that Fst-induced adipose browning protects against the development of atherosclerosis. We will test our hypothesis under these Specific Aims: Aim 1: We will determine the role of Fst in adipose browning, lipoprotein metabolism and development of atherosclerosis. We will determine the effects of Fst tissue and systemic overexpression using mouse low density lipoprotein receptor (LDLR)-deficient WT and adipose-specific transgenic (FstAdQTg ) mice, and adeno-associated virus 1 (AAV1)-FST344 injected LDLR-/- mice respectively to determine the role of Fst on i) adipose browning, plasma lipoprotein, TG, and TC levels, ii) tissue (adipose, aorta, and liver), plasma metabolites and iii) gene expression during diet-induced development of dyslipidemia and atherosclerosis. Effect of transient loss of Fst on browning, lipoprotein metabolism and atherosclerosis progression will be analyzed in mPCSK9 injected Fstfl/fl / CreAdQ mice. Aim 2: We will determine the molecular mechanisms by which Fst confer the pro-browning and anti-atherogenic effects. We will test whether arginase 1 (Arg 1)/beta-adrenergic receptor (β-AR)/ p38MAPK/FGF21 signaling pathway confer Fst-induced pro-browning and antiatherogenic action in the three animal models. We will utilize gene aortic lesion and gene metabolite correlation dataset obtained from system genetics approach of atherosclerosis hybrid mouse diversity panel (HMDP) to identify key Fst-regulated genes and metabolites. We will perform comprehensive RNA-sequence analysis, and tissue and plasma metabolite analysis combined with pharmacological inhibition studies to identify novel genes and metabolites involved during Fst-induced adipose browning and its anti-atherogenic actions. Our proposed studies will provide significant novel insights into the pro-browning and anti-atherogenic role of Fst and identify key molecular targets involved in favorably altering lipoprotein metabolism and the development of atherosclerosis. Inhibition of atherosclerosis development by using Fst protein/peptide is an attractive therapeutic avenue. Data obtained after successful completion of this project provide rationale for therapeutic drug design for the treatment of atherosclerosis and enable us to submit highly competitive RO1-like grant applications.
摘要

项目成果

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RAJAN SINGH其他文献

RAJAN SINGH的其他文献

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{{ truncateString('RAJAN SINGH', 18)}}的其他基金

Follistatin regulation of energy and lipid metabolism during progression of atherosclerosis
卵泡抑素对动脉粥样硬化进展过程中能量和脂质代谢的调节
  • 批准号:
    10618987
  • 财政年份:
    2022
  • 资助金额:
    $ 14.88万
  • 项目类别:
Follistatin promotes browning and influences energy metabolism
卵泡抑素促进褐变并影响能量代谢
  • 批准号:
    8740378
  • 财政年份:
    2014
  • 资助金额:
    $ 14.88万
  • 项目类别:
Role of Follistatin during Androgen Regulation of Body Composition
卵泡抑素在雄激素调节身体成分中的作用
  • 批准号:
    7886057
  • 财政年份:
    2009
  • 资助金额:
    $ 14.88万
  • 项目类别:
Role of Follistatin during Androgen Regulation of Body Composition
卵泡抑素在雄激素调节身体成分中的作用
  • 批准号:
    7427275
  • 财政年份:
    2008
  • 资助金额:
    $ 14.88万
  • 项目类别:
Role of Follistatin during Androgen Regulation of Body Composition
卵泡抑素在雄激素调节身体成分中的作用
  • 批准号:
    7892286
  • 财政年份:
    2008
  • 资助金额:
    $ 14.88万
  • 项目类别:
Role of Follistatin during Androgen Regulation of Body Composition
卵泡抑素在雄激素调节身体成分中的作用
  • 批准号:
    8116489
  • 财政年份:
    2008
  • 资助金额:
    $ 14.88万
  • 项目类别:
Role of Follistatin during Androgen Regulation of Body Composition
卵泡抑素在雄激素调节身体成分中的作用
  • 批准号:
    7666070
  • 财政年份:
    2008
  • 资助金额:
    $ 14.88万
  • 项目类别:

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成纤维细胞生长因子 8b 将棕色脂肪细胞募集到内脏白色脂肪组织中
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路易斯安那 COBRE:P1:在白色脂肪组织中诱导产热棕色脂肪细胞
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