Managing Atherosclerosis by Modulating HDL Function

通过调节 HDL 功能来治疗动脉粥样硬化

基本信息

  • 批准号:
    10595029
  • 负责人:
  • 金额:
    $ 77.36万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2013
  • 资助国家:
    美国
  • 起止时间:
    2013-06-01 至 2026-03-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY/ABSTRACT Atherosclerosis is the leading cause of human mortality worldwide. There has been a great interest in developing novel therapeutics for this disease that function via an orthogonal mechanism of action to currently available drugs. One promising strategy is to enhance the function of high-density lipoproteins (HDLs). HDLs facilitate reverse cholesterol transport (RCT) to transfer excess cholesterol from peripheral tissues to the liver for elimination. The proposed research, supported by strong recent progress, seeks to advance a novel supramolecular strategy for improving HDL function in vivo to combat atherosclerosis. The proposed studies build on the successes of our research program, funded by an NHLBI R01 grant over the past eight years. Despite substantial progress in the field of apolipoprotein mimetic peptides, including evaluation of several candidates in phase 1 and 2 human clinical trials, the inherent pharmacological shortcomings typically associated with linear peptides have been a major impediment to advancing HDL- modulating peptides through the clinic. Our proposed research seeks to develop a novel class of chemotypes that can recapitulate the functional attributes of helical lipoprotein mimetics, but without their inherent limitations. We have established that appropriately designed eight-residue self-assembling cyclic D,L-a-peptides are effective HDL modulating agents that can remodel human and mouse plasma HDLs and enhance cholesterol efflux from macrophage cells. These peptides specifically increase the level of pre-beta HDL particles (subspecies of HDLs considered to be the most anti-atherogenic), reduce LDL-cholesterol and triglyceride levels, and promote anti-inflammatory effects with concomitant prevention of atherosclerosis in mouse disease models. The abiotic structure of cyclic D,L-a-peptides overcomes many of the shortcomings typically associated with linear peptides, such as low serum/plasma stability and high production costs, among others. Specific aims 1 and 2 of the proposed research involve i) implementing a series of mechanism-based functional bioassays and biophysical assays to optimize and better characterize the mode of action of the lead compounds, and ii) establishing in vivo pharmacology, toxicology, and efficacy of selected cyclic peptides in two leading mouse models of atherosclerosis. Specific aim 3 of the proposed research is based on an unexpected, remarkable observation made in the course of our recent studies. We have discovered that trifluoroacetate (TFA), administered orally or parenterally, causes dose-dependent reductions in plasma cholesterol levels and prevents the development of atherosclerosis in vivo. The implications of this discovery are potentially broad because nearly all synthetic peptides, employed across diverse biological settings, contain TFA counterions resulting from purification by preparative HPLC. As such, the effects of TFA on cellular metabolism in vitro and in vivo must be characterized and understood. We propose a series of hypothesis-based in vitro and in vivo studies to define the mechanism and generality of the observed TFA-mediated anti-atherosclerosis effects.
项目总结/文摘

项目成果

期刊论文数量(0)
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会议论文数量(0)
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M. Reza Ghadiri其他文献

M. Reza Ghadiri的其他文献

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{{ truncateString('M. Reza Ghadiri', 18)}}的其他基金

Toward Personalized Therapeutics: Directed Remodeling of the Gut Microbiome to Treat Atherosclerosis
走向个性化治疗:定向重塑肠道微生物组来治疗动脉粥样硬化
  • 批准号:
    10379067
  • 财政年份:
    2020
  • 资助金额:
    $ 77.36万
  • 项目类别:
Toward Personalized Therapeutics: Directed Remodeling of the Gut Microbiome to Treat Atherosclerosis
走向个性化治疗:定向重塑肠道微生物组来治疗动脉粥样硬化
  • 批准号:
    10600843
  • 财政年份:
    2020
  • 资助金额:
    $ 77.36万
  • 项目类别:
Managing Atherosclerosis by Modulating HDL Function
通过调节 HDL 功能来治疗动脉粥样硬化
  • 批准号:
    10446767
  • 财政年份:
    2013
  • 资助金额:
    $ 77.36万
  • 项目类别:
Managing Atherosclerosis by Modulating HDL Function
通过调节 HDL 功能来治疗动脉粥样硬化
  • 批准号:
    8666812
  • 财政年份:
    2013
  • 资助金额:
    $ 77.36万
  • 项目类别:
Managing Atherosclerosis by Modulating HDL Function
通过调节 HDL 功能来治疗动脉粥样硬化
  • 批准号:
    10065511
  • 财政年份:
    2013
  • 资助金额:
    $ 77.36万
  • 项目类别:
Managing Atherosclerosis by Modulating HDL Function
通过调节 HDL 功能来治疗动脉粥样硬化
  • 批准号:
    8480969
  • 财政年份:
    2013
  • 资助金额:
    $ 77.36万
  • 项目类别:
Synthesis and Application of Novel Apolipoprotein Mimetics
新型载脂蛋白模拟物的合成及应用
  • 批准号:
    8269810
  • 财政年份:
    2011
  • 资助金额:
    $ 77.36万
  • 项目类别:
Synthesis and Application of Novel Apolipoprotein Mimetics
新型载脂蛋白模拟物的合成及应用
  • 批准号:
    8110380
  • 财政年份:
    2011
  • 资助金额:
    $ 77.36万
  • 项目类别:
Single-Molecule DNA Sequencing with Engineered Nanopores
使用工程化纳米孔进行单分子 DNA 测序
  • 批准号:
    8499385
  • 财政年份:
    2005
  • 资助金额:
    $ 77.36万
  • 项目类别:
Single-Molecule DNA Sequencing with Engineered Nanopores
利用工程化纳米孔进行单分子 DNA 测序
  • 批准号:
    8748877
  • 财政年份:
    2005
  • 资助金额:
    $ 77.36万
  • 项目类别:

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