AIBP and Endothelial Function

AIBP 和内皮功能

基本信息

  • 批准号:
    8885205
  • 负责人:
  • 金额:
    $ 51.56万
  • 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:
    2015-04-01 至 2019-03-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Inflammation and lipid accumulation in the vascular wall constitute critical events in initiation and progression of cardiovascular disease, manifested in myocardial infarction and stroke in more than a half of the US population. Activated endothelial cells (EC) secrete chemokines and express adhesion molecules to recruit leukocytes to the vascular wall. Oxidized LDL and dysfunctional HDL play a major role in EC-mediated inflammation, whereas functional HDL preserves the EC integrity and prevents inflammatory responses. One of the major mechanisms by which HDL exerts its protective function is cholesterol efflux from the plasma membrane of EC. We discovered that apoA-I binding protein (AIBP) significantly improves HDL function by accelerating cholesterol efflux from EC. AIBP is a secreted protein and its effect on EC is paracrine and non-cell autonomous. These findings open the possibility of using AIBP or AIBP-derived peptides as a therapy to improve the cholesterol efflux function of HDL and thereby prevent and/or reverse vascular pathology. Here we propose to test the hypothesis that AIBP reduces EC inflammatory responses via modulation of cholesterol efflux and lipid rafts. We will test this hypothesis in cellular models as well as in aorta explants, by measuring expression of cytokines and adhesion molecules, probing relevant signaling pathways, detecting ROS, apoptosis and autophagy, and assessing LDL transcytosis and monocyte adhesion. Further, we will determine effects of systemic and tissue-specific AIBP deficiency on endothelial function. We have developed Aibp LoxP and Aibp knockout mice, which are viable and fertile. AIBP expression has been detected in macrophages and vascular smooth muscle cells (VSMC) of mouse atherosclerotic lesions. Thus, we propose that AIBP secreted by macrophages and/or VSMC protects aortic EC and that deletion of Aibp in these cells will lead to exacerbated EC inflammatory responses and increased atherosclerosis burden. We also hypothesize that, conversely, raising AIBP levels will improve endothelial function and reduce inflammation. The hypothesis will be tested in vivo with mouse and zebrafish animal models and ex vivo with human plasma samples obtained from patients with dyslipidemia and/or cardiovascular disease (CVD). In a hypercholesterolemic zebrafish model, we expect that conditional expression of Aibp will reduce vascular lipid accumulation, foam cell formation, membrane lipid order in EC, and vascular permeability. In a hypercholesterolemic mouse model, we expect that infusion of recombinant AIBP, alone or in combination with apoA-I, will reduce EC inflammation and atherosclerosis. In addition, human plasma and HDL isolated from CVD patients will be supplemented with recombinant AIBP and tested for their effect on monocyte adhesion to EC. We expect that AIBP will improve protective properties of dysfunctional HDL. Results of these experiments, if positive, will facilitate future development of AIBP-based therapeutic applications.


项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(1)

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Yury Miller其他文献

Yury Miller的其他文献

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{{ truncateString('Yury Miller', 18)}}的其他基金

AIBP and regulation of neuropathic pain
AIBP 和神经性疼痛的调节
  • 批准号:
    9816541
  • 财政年份:
    2019
  • 资助金额:
    $ 51.56万
  • 项目类别:
Reversal of preexisting neuropathic pain by spinal delivery of AIBP
通过脊髓输送 AIBP 逆转先前存在的神经性疼痛
  • 批准号:
    9750836
  • 财政年份:
    2018
  • 资助金额:
    $ 51.56万
  • 项目类别:
Reversal of preexisting neuropathic pain by spinal delivery of AIBP
通过脊髓输送 AIBP 逆转先前存在的神经性疼痛
  • 批准号:
    10197482
  • 财政年份:
    2018
  • 资助金额:
    $ 51.56万
  • 项目类别:
Cholesterol Regulation of Inflammatory Macrophages in Atherosclerosis
动脉粥样硬化中炎症巨噬细胞的胆固醇调节
  • 批准号:
    10188606
  • 财政年份:
    2017
  • 资助金额:
    $ 51.56万
  • 项目类别:
AIBP therapy
AIBP治疗
  • 批准号:
    9240927
  • 财政年份:
    2017
  • 资助金额:
    $ 51.56万
  • 项目类别:
AIBP therapy
AIBP治疗
  • 批准号:
    10551912
  • 财政年份:
    2017
  • 资助金额:
    $ 51.56万
  • 项目类别:
AIBP therapy
AIBP治疗
  • 批准号:
    10331313
  • 财政年份:
    2017
  • 资助金额:
    $ 51.56万
  • 项目类别:
Project 2: Cholesterol Regulation of Inflammatory Macrophages in Atherosclerosis
项目2:动脉粥样硬化中炎症巨噬细胞的胆固醇调节
  • 批准号:
    10334095
  • 财政年份:
    2017
  • 资助金额:
    $ 51.56万
  • 项目类别:
AIBP and Endothelial Function
AIBP 和内皮功能
  • 批准号:
    9039657
  • 财政年份:
    2015
  • 资助金额:
    $ 51.56万
  • 项目类别:
Early Forms of Oxidized LDL, TLRs and Atherosclerosis
氧化 LDL、TLR 和动脉粥样硬化的早期形式
  • 批准号:
    7839765
  • 财政年份:
    2009
  • 资助金额:
    $ 51.56万
  • 项目类别:

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