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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：
M. Reza Ghadiri
金额：
$ 77.36万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
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

来源：
https://reporter.nih.gov/project-details/10595029
关键词：
Abate Acetyl Coenzyme A Address Adipocytes Adverse effects Amino Acids Animals Antiatherogenic Antiinflammatory Effect Apolipoprotein A-I Apolipoprotein E Apolipoproteins Atherosclerosis Binding Biological Biological Assay Biological Availability Biology Biophysics Cells Cholesterol Clinic Clinical Trials Coenzyme A Cyclic Peptides Data Development Disease Disease model Dose Dyslipidemias Evaluation Family Funding Goals Grant High Density Lipoproteins High Pressure Liquid Chromatography Human In Vitro Knockout Mice LDL Cholesterol Lipoproteins Lead Lipids Lipolysis Lipoproteins Liver Macrophage Marketing Mediating Metabolic Metabolism Molecular Molecular Structure Mus National Heart, Lung, and Blood Institute Oral Oral Administration Peptide Nanotubes Peptide Synthesis Peptides Periodicity Peripheral Peroxisome Proliferation Pharmaceutical Preparations Pharmacology Phase Plasma Population Prevention Process Production Proteins Research Route Series Serum Side Structure Therapeutic Therapeutic Agents Tissues Toxic effect Toxicology Trifluoroacetate Triglycerides amphiphilicity analog combat cost design efficacy study gut microbiome human mortality human tissue improved in vitro Assay in vivo inhibitor interest intraperitoneal lead optimization mimetics mouse model novel novel therapeutics organic acid particle peptidomimetics pharmacologic pre-beta high-density lipoprotein prevent programs reagent standard receptor reverse cholesterol transport self assembly stem success synthetic peptide targeted treatment transcriptome sequencing

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.

项目概要/摘要动脉粥样硬化是全世界人类死亡的主要原因。人们对此产生了极大的兴趣开发针对这种疾病的新疗法，通过目前的正交作用机制发挥作用可用药物。一种有前途的策略是增强高密度脂蛋白（HDL）的功能。高密度脂蛋白促进胆固醇反向转运（RCT），将多余的胆固醇从外周组织转移到肝脏用于消除。拟议的研究得到了近期强劲进展的支持，旨在推进一种新颖的研究改善体内HDL功能以对抗动脉粥样硬化的超分子策略。拟议的研究建立在我们研究计划的成功之上，该计划由 NHLBI R01 拨款资助过去八年。尽管载脂蛋白模拟肽领域取得了实质性进展，包括在 1 期和 2 期人体临床试验中对数个候选药物进行评估，其固有的药理学通常与线性肽相关的缺点一直是推进 HDL- 的主要障碍通过临床调节肽。我们提出的研究旨在开发一类新型化学型它可以概括螺旋脂蛋白模拟物的功能属性，但没有其固有的局限性。我们已经确定，适当设计的八残基自组装环状 D,L-a 肽是有效的 HDL 调节剂，可以重塑人和小鼠血浆 HDL 并提高胆固醇从巨噬细胞流出。这些肽专门增加前β HDL 颗粒的水平（高密度脂蛋白亚种被认为是最具抗动脉粥样硬化作用的），降低低密度脂蛋白胆固醇和甘油三酯水平，在小鼠疾病模型中促进抗炎作用，同时预防动脉粥样硬化。环状 D,L-a-肽的非生物结构克服了许多通常与线性肽，例如低血清/血浆稳定性和高生产成本等。拟议研究的具体目标 1 和 2 涉及 i) 实施一系列基于机制的措施功能生物测定和生物物理测定，以优化和更好地表征先导物的作用模式化合物，以及 ii) 确定选定环肽在两种药物中的体内药理学、毒理学和功效主要的动脉粥样硬化小鼠模型。拟议研究的具体目标 3 是基于一个意想不到的、我们在最近的研究过程中取得了显着的观察结果。我们发现三氟乙酸（TFA），口服或肠胃外给药，导致血浆胆固醇水平呈剂量依赖性降低，并预防体内动脉粥样硬化的发展。这一发现的影响可能是广泛的，因为几乎所有用于不同生物环境的合成肽都含有 TFA 抗衡离子通过制备型HPLC纯化。因此，TFA 对体外和体内细胞代谢的影响必须是特征和理解。我们提出了一系列基于假设的体外和体内研究来定义观察到的 TFA 介导的抗动脉粥样硬化作用的机制和一般性。