ABCA1 agonist peptides for therapeutic use

描述(申请人提供)：高密度脂蛋白(高密度脂蛋白)具有预防动脉粥样硬化的有益活性。高密度脂蛋白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，促进抗动脉粥样硬化的反向胆固醇运输(RCT)途径。载脂蛋白A-I和载脂蛋白E对细胞胆固醇外流的刺激构成了RCT的限速步骤，它产生高密度脂蛋白并逆转巨噬细胞泡沫细胞表型。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确定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，确定支配和指导随机对照试验过程的基本原则和力量。这些信息将被转化为治疗方法，以对抗胆固醇稳态异常的疾病。在比较分析apoA-I和E-C末端结构域的基础上，构建了ABCA1的高亲和力功能配体。这项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多肽是否会增加血浆高密度脂蛋白浓度，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中去除多余的胆固醇具有广泛的生物学和临床意义。基于由高密度脂蛋白形成的小肽，将开发一种新的治疗方法。这项研究可能会对公众健康产生很大影响，因为治疗方法将服从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.