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Nutrient-sensing GHS-R in macrophage reprogramming and inflamm-aging

Nutrient-sensing GHS-R in macrophage reprogramming and inflamm-aging
巨噬细胞重编程和炎症衰老中的营养感应 GHS-R
批准号:
10436515
负责人:
YUXIANG SUN
金额:
$5.3万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-07-01 至 2024-04-30

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英文摘要
Project Summary Chronic over-nutrition and obesity induce low-grade inflammation in tissues such as adipose tissue and liver, the inflammation leads to further metabolic dysfunctions in these tissues. This metabolically-triggered inflammation is termed "meta-inflammation", which underlies pathological processes of many chronic diseases such obesity, insulin resistance, and diabetes. Macrophages are key immune-modulators of meta-inflammation, comprised of two main subtypes: pro-inflammatory M1 and anti-inflammatory M2. Emerging evidences suggest that promoting macrophage anti-inflammatory polarization has exciting potential for reversing the pathology of meta-inflammation. However, the regulatory mechanisms of macrophage polarization are not well understood. G-protein-coupled receptor, growth hormone secretagogue receptor (GHS-R), is a known receptor for nutrient- sensing gut hormone ghrelin. Ghrelin promotes obesity and insulin resistance. Global GHS-R ablation protects against diet-induced obesity and insulin resistance in aging, showing reduced inflammation in adipose tissue and liver. Cell-based studies further suggest that GHS-R has cell-autonomous effects in macrophages, and GHS-R knockdown decreases endotoxin-induced macrophage pro-inflammatory shift. The hypothesize of this proposal is that GHS-R is a key regulator of meta-inflammation, contributing to the pathogenesis of obesity and nonalcoholic steatohepatitis (NASH); GHS-R reprograms macrophage polarization toward a pro-inflammatory state, leading to inflammation and metabolic dysfunctions in adipose tissue and liver. To unravel the roles and pertinent mechanisms of GHS-R in macrophage polarization, newly-generated myeloid- specific GHS-R knockout mice will be used. The following comprehensive and complementary Specific Aims will be conducted: 1. Determine whether GHS-R promotes pro-inflammatory polarization of macrophages, and increases inflammation and lipid deposition in adipose tissue and liver (in vivo studies). 2. Examine whether GHS-R cell-autonomously regulates macrophage polarization, and GHS-R activation in macrophages promotes inflammation and enhances lipotoxicity in adipocytes and hepatocytes via endocrine and/or paracrine actions (ex vivo studies). 3. Investigate molecular mechanisms involved in GHS-R mediated macrophage polarization. We postulate that GHS-R metabolically reprograms macrophages; GHS-R, via insulin signaling, modulates signaling pathways to govern fatty acid oxidation, glucose metabolism, and mitochondrial function of macrophages. This proposal will shed light on a new paradigm for regulating macrophage polarization, and will likely uncover a novel regulatory mechanism linking nutrient sensing, inflammation and metabolism. This proposal will also provide “proof-of-concept” evidence for whether targeting GHS-R in macrophages would be a unique and powerful strategy for combating obesity and inflammation.
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Cardiac Macrophage Plasticity in Sepsis-induced Cardiomyopathy
  • 批准号:
    10728175
  • 项目类别:
  • 资助金额:
    $19.91万
  • 财政年份:
    2023
  • 负责人:
    YUXIANG SUN
  • 依托单位:
The role of GHS-R in macrophage reprogramming during meta-inflammation
  • 批准号:
    10194483
  • 项目类别:
  • 资助金额:
    $31.28万
  • 财政年份:
    2019
  • 负责人:
    YUXIANG SUN
  • 依托单位:
Nutrient-sensing GHS-R in macrophage reprogramming and inflamm-aging
  • 批准号:
    10425305
  • 项目类别:
  • 资助金额:
    $30.6万
  • 财政年份:
    2019
  • 负责人:
    YUXIANG SUN
  • 依托单位:
Nutrient sensing ghrelin signaling - a novel pathogenic factor for Alzheimer’s Disease
  • 批准号:
    10285433
  • 项目类别:
  • 资助金额:
    $37.88万
  • 财政年份:
    2019
  • 负责人:
    YUXIANG SUN
  • 依托单位:
国内基金
海外基金
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