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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.

项目总结/文摘