ABCA1 agonist peptides for therapeutic use

描述（由申请人提供）：高密度脂蛋白（HDL）具有预防动脉粥样硬化的有益活性。HDL的有益作用部分与其组成蛋白有关，如载脂蛋白（apo） A-I和E，它们促进抗动脉粥样硬化逆向胆固醇转运（RCT）途径。apoA-I和E对细胞胆固醇外排的刺激构成了RCT中产生HDL和逆转巨噬细胞泡沫细胞表型的限速步骤。这些事件需要atp结合盒转运体A1 （ABCA1）。因此，ABCA1具有临床相关性，是对抗动脉粥样硬化治疗干预的一个有吸引力的靶点。这些研究的长期目标是试图确定载脂蛋白家族成员与膜转运蛋白（如ABCA1）相互作用的分子基础，确定控制和指导RCT过程的基本原理和力量。这些信息将被转化为治疗方法，以对抗异常胆固醇稳态疾病。通过对apoA-I和E - c末端结构域的比较分析，构建了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的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消退。这项研究对于了解高密度脂蛋白如何从动脉壁去除多余的胆固醇具有广泛的生物学和临床意义。一种新的治疗方法将基于由HDL蛋白配制的小肽而开发。这项研究可能对公众健康产生重大影响，因为这种治疗方法将适用于动脉粥样硬化的广泛治疗。

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.