ABCA1 agonist peptides for therapeutic use

用于治疗用途的 ABCA1 激动剂肽

基本信息

批准号：
7257930
负责人：
JOHN K BIELICKI
金额：
$ 20.36万
依托单位：
UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-01 至 2009-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7257930
关键词：
ATP binding cassette transporter 1 ATP-Binding Cassette Transporters Affinity Agonist Amino Acids Antiatherogenic Apolipoprotein A-I Apolipoproteins Arterial Fatty Streak Arteries Atherosclerosis Biological C-terminal Cells Cholesterol Cholesterol Homeostasis Class Consensus Diet Disease Disease regression Event Exhibits Family member Feces Foam Cells High Density Lipoproteins Human Integral Membrane Protein Kinetics Length Ligands Liver Low Density Lipoprotein Receptor Mediating Membrane Transport Proteins Molecular Mus Nature Pathway interactions Peptides Performance Peripheral Phenotype Plasma Play Proteins Public Health Rate Research Role Sterols Testing Therapeutic Therapeutic Intervention Therapeutic Uses Translating Transport Process base clinically relevant comparative feeding human disease improved in vivo macrophage mouse model novel novel therapeutics reverse cholesterol transport

项目摘要

DESCRIPTION (provided by applicant): High density lipoproteins (HDL) possess beneficial activities that protect against atherosclerosis. The beneficial effects of HDL are related, in part, to its constituent proteins, such as apolipoprotein(apo) A-I and E, that facilitate the antiatherogenic reverse cholesterol transport (RCT) pathway. Stimulation of cellular cholesterol efflux by apoA-I and E constitutes the rate-limiting step in RCT that generates HDL and reverses the macrophage foam-cell phenotype. These events require the ATP-binding cassette transporter A1 (ABCA1). As a result, ABCA1 is clinically relevant and represents an attractive target for therapeutic interventions to combat atherosclerosis. The long-term objectives of these studies seek to define the molecular basis by which apolipoprotein family members interact with membrane transporters such as ABCA1, identifying fundamental principles and forces that govern and direct the RCT process. The information will be translated into therapeutics to combat diseases of aberrant cholesterol homeostasis. Based on comparative analyses of apoA-I and E C-terminal domains, a high-affinity functional-ligand for ABCA1 was created. The proposed studies will utilize a mouse model of human disease to test whether this novel consensus peptide increases plasma HDL concentrations, promotes RCT activity in vivo, and stimulates the regression of atherosclerotic lesions. The research is of broad biological- and clinical-relevance for understanding how HDL proteins remove excess cholesterol from the artery wall. A new class of therapeutics will be developed based on small peptides formulated from HDL proteins. The research is likely to have a high impact on public health, since the therapeutics will be amenable to the widespread treatment of atherosclerosis.

描述（由申请人提供）：高密度脂蛋白（HDL）具有可防止动脉粥样硬化的有益活动。 HDL的有益作用部分与其成分蛋白（例如载脂蛋白（APO）A-I和E）相关，促进了抗抗毒性反向胆固醇转运（RCT）途径。通过ApoA-I和E刺激细胞胆固醇外排，构成了RCT中限制的步骤，该步骤会产生HDL并逆转巨噬细胞泡沫 - 细胞表型。这些事件需要ATP结合盒式转运蛋白A1（ABCA1）。结果，ABCA1在临床上是相关的，代表了对抗动脉粥样硬化的治疗干预措施的有吸引力的靶标。这些研究的长期目标旨在定义载脂蛋白家族成员与ABCA1等膜转运蛋白相互作用的分子基础，从而确定了控制和指导RCT过程的基本原理和力量。该信息将转化为治疗剂，以打击异常胆固醇稳态的疾病。基于对ApoA-I和E C末端结构域的比较分析，创建了ABCA1的高亲和力功能 - 配体。拟议的研究将利用人类疾病的小鼠模型来测试这种新型共识肽是否会增加血浆HDL浓度，促进体内RCT活性并刺激动脉粥样硬化病变的回归。这项研究是广泛的生物学和临床 - 相关性，用于理解HDL蛋白如何从动脉壁中去除多余的胆固醇。将根据由HDL蛋白配制的小肽开发新的治疗剂。这项研究可能对公共卫生产生很大的影响，因为该治疗剂将适合广泛治疗动脉粥样硬化。