Cellular Lipids and Leukocyte Function

细胞脂质和白细胞功能

基本信息

  • 批准号:
    9313269
  • 负责人:
  • 金额:
    $ 29.03万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-08-01 至 2019-07-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Sepsis is characterized by the release of bacterial structural components and toxins that activate inflammatory cascades in target cells. The recruitment of neutrophils and their binding to the vascular endothelium is an important, early response to sepsis. Neutrophils and resident macrophages initiate repair processes via the secretion of cytokines, chemokines and digestive enzymes. Dysregulation of the immune response, however, can lead to widespread and uncontrolled inflammatory injury characterized by leukocytosis (neutrophilia/monocytosis). This dysregulation results in multiple organ dysfunction syndrome (MODS) with the transition to overt septic shock. Respiratory failure progresses rapidly and is associated with approximately 40- 50% mortality. HDL serves as a carrier for diverse proteins, including apolipoprotein (apo) A-I and apoE, that play a role in mediating reverse cholesterol transport. Several studies suggest that apoE exerts anti-inflammatory effects, including the modulation of immune cell function, that are independent of its ability to lower plasma cholesterol levels. In this regard, apoE was recently shown to limit th expansion of hematopoietic stem and multipotential progenitor cells (HSPCs), resulting in a decrease in neutrophil and monocyte proliferation. The inhibitory effect of apoE on leukocyte activation was linked to a reduction in cellular cholesterol content per se. It is proposed that HDL-associated apoE plays a critical role in reducing inflammatory cell injury in the context of sepsis. This protective effect of apoE, however, may be limited by reduced levels of HDL that characterize sepsis. Preliminary data presented in the application show that a synthetic peptide (Ac-hE18A-NH2) that mimics effects of native apoE prevents the activation of leukocytes and improves survival in a rodent model of sepsis. Ac-hE18A-NH2 also induces the release of preß-HDL particles containing the antioxidant paraoxonase and apoE itself. Our data also show that apoE mimetics bind to cell surface proteoglycans and mediate cholesterol efflux from leukocytes, a response that is associated with a reduction in lipopolysaccharide-induced cytokine/chemokine release. In this application, we will test the novel hypothesis that Ac-hE18A-NH2 and related apoE mimetic peptides attenuate sepsis-induced inflammatory injury by inhibiting HSPC expansion and leukocyte proliferation/activation by a mechanism involving a reduction in cellular cholesterol content. Additional studies will test whether in vitro treatment with apoE mimetic peptides alters the phenotype/function of leukocytes isolated from septic patients.


项目成果

期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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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

HDL and Cellular Repair Mechanisms
HDL 和细胞修复机制
  • 批准号:
    9215669
  • 财政年份:
    2016
  • 资助金额:
    $ 29.03万
  • 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:
    $ 29.03万
  • 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:
    $ 29.03万
  • 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:
    $ 29.03万
  • 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:
    $ 29.03万
  • 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:
    $ 29.03万
  • 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:
    $ 29.03万
  • 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:
    $ 29.03万
  • 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:
    $ 29.03万
  • 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:
    $ 29.03万
  • 项目类别:

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