HDL and Cellular Repair Mechanisms

HDL 和细胞修复机制

基本信息

  • 批准号:
    9215669
  • 负责人:
  • 金额:
    $ 33.08万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-04-01 至 2020-03-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Under normal physiological conditions, high density lipoprotein (HDL) plays an important role in regulating cellular cholesterol homeostasis and also possesses anti-inflammatory properties. Beneficial properties of HDL have been ascribed, in large part, to apolipoprotein A-I (apoA-I). Inflammation, however, can convert HDL into a dysfunctional lipoprotein particle that is depleted of apoA-I and enriched with acute phase proteins. Therapeutic approaches that increase plasma levels of functional HDL reduce ischemia-reperfusion (I/R) injury and other inflammatory disorders. Previous studies show that apoA-I mimetic peptides exert anti-inflammatory effects by increasing functional HDL levels and inhibiting monocyte/macrophage (MΦ) infiltration in tissues. In this regard, it was shown that the synthetic peptide 4F, which mimics functional properties of apoA-I, alters the metabolic profile of human monocyte-derived MΦs, resulting in the adoption of an anti-inflammatory M2 phenotype. These responses were associated with up-regulation of genes that regulate mitochondrial respiration, resulting in an increase in oxidative phosphorylation and ATP formation. In this application, we present data showing that 4F reduces hepatocellular injury in a murine model of hepatic I/R injury. The protective response to 4F treatment is thought to be due to an increase in circulating levels of functional HDL. Specifically, we show that Kupffer cells (KCs), tissue resident MΦs, adopt an anti-inflammatory phenotype. HDL may induce this response by increasing mitochondrial respiration and ATP formation, processes that support the induction of an anti-inflammatory wound healing response. Second, HDL may improve survival in hepatocytes via induction of autophagy, resulting in the clearance of damaged mitochondria and their replacement with new functional mitochondria. A mouse model of liver I/R will be used to test these hypotheses, and underlying mechanisms will be defined in cell culture systems.
 描述(由申请人提供):在正常生理条件下,高密度脂蛋白(HDL)在调节细胞胆固醇稳态中起重要作用,并且还具有抗炎特性。HDL的有益特性在很大程度上归因于载脂蛋白A-I(apoA-I)。然而,炎症可以将HDL转化为功能障碍的脂蛋白颗粒,其耗尽apoA-I并富含急性期蛋白。增加功能性HDL的血浆水平的治疗方法减少缺血-再灌注(I/R)损伤和其它炎性病症。以往的研究表明apoA-I模拟肽通过提高HDL水平和抑制单核/巨噬细胞(MΦ)浸润发挥抗炎作用。在这方面,有人指出, 模拟apoA-I功能特性的合成肽4F改变了apoA-I的代谢特征, 人单核细胞来源的MΦ,导致采用抗炎M2表型。这些反应与调节线粒体呼吸的基因上调有关,导致氧化磷酸化和ATP形成增加。在本申请中,我们提供的数据表明,4F减少肝I/R损伤的小鼠模型中的肝细胞损伤。对4F治疗的保护性反应被认为是由于功能性HDL的循环水平增加。具体来说,我们发现枯否细胞(KCs),组织驻留MΦ,采用抗炎表型。HDL可以通过增加线粒体呼吸和ATP形成来诱导这种反应,这是支持诱导抗炎伤口愈合反应的过程。第二,HDL可以通过诱导自噬来改善肝细胞的存活,导致受损线粒体的清除和新功能线粒体的替代。将使用肝脏I/R的小鼠模型来测试这些假设,并在细胞培养系统中定义潜在的机制。

项目成果

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G M ANANTHARAMAIAH其他文献

G M ANANTHARAMAIAH的其他文献

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{{ truncateString('G M ANANTHARAMAIAH', 18)}}的其他基金

Cellular Lipids and Leukocyte Function
细胞脂质和白细胞功能
  • 批准号:
    9313269
  • 财政年份:
    2015
  • 资助金额:
    $ 33.08万
  • 项目类别:
Modulators of HDL Structure-Function
HDL 结构-功能调节剂
  • 批准号:
    8242747
  • 财政年份:
    2011
  • 资助金额:
    $ 33.08万
  • 项目类别:
Peptide Synthesis and Purification Core Facility
肽合成与纯化核心设施
  • 批准号:
    8242749
  • 财政年份:
    2011
  • 资助金额:
    $ 33.08万
  • 项目类别:
Apo E mimetics reduce cholesterol and improve HDL function
Apo E 模拟物可降低胆固醇并改善 HDL 功能
  • 批准号:
    7867924
  • 财政年份:
    2008
  • 资助金额:
    $ 33.08万
  • 项目类别:
Peptide Synthesis and Purification Core Facility
肽合成与纯化核心设施
  • 批准号:
    7466200
  • 财政年份:
    2008
  • 资助金额:
    $ 33.08万
  • 项目类别:
Apo E mimetics reduce cholesterol and improve HDL function
Apo E 模拟物可降低胆固醇并改善 HDL 功能
  • 批准号:
    7666804
  • 财政年份:
    2008
  • 资助金额:
    $ 33.08万
  • 项目类别:
Apo E mimetics reduce cholesterol and improve HDL function
Apo E 模拟物可降低胆固醇并改善 HDL 功能
  • 批准号:
    8111688
  • 财政年份:
    2008
  • 资助金额:
    $ 33.08万
  • 项目类别:
Modulators of HDL Structure-Function
HDL 结构-功能调节剂
  • 批准号:
    7466153
  • 财政年份:
    2008
  • 资助金额:
    $ 33.08万
  • 项目类别:
Modulators of HDL structure-function
HDL结构-功能调节剂
  • 批准号:
    7298870
  • 财政年份:
    2007
  • 资助金额:
    $ 33.08万
  • 项目类别:
Enhanced Hepatic Lipoprotein Uptake and Atherogenesis
增强肝脏脂蛋白摄取和动脉粥样硬化形成
  • 批准号:
    6527643
  • 财政年份:
    2001
  • 资助金额:
    $ 33.08万
  • 项目类别:

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