miR-33 Pathway Inhibition for Improving HDL Functionality

 描述(申请人提供)：虽然大量的流行病学研究表明，高水平的高密度脂蛋白-C与心血管疾病的预防有关，但最近提高高密度脂蛋白的疗法在减少临床事件方面的失败使整个高密度脂蛋白范例受到了质疑。这些研究强调了更好地了解高密度脂蛋白发挥动脉粥样硬化保护作用的机制的迫切需要，以便我们能够设计利用这些特性并提供最大临床益处的疗法。对动物和人类的实验研究表明，增加高密度脂蛋白颗粒数量或促进胆固醇反向转运(RCT)的治疗方法具有动脉粥样硬化保护作用。我们实验室等人发现，microRNA-33a/b(miR-33)抑制了这些通路中的关键基因，包括ABCA1、Abcg1、NPC1，这是我们对高密度脂蛋白生物发生和胆固醇外流调控的一大进步。在对小鼠和非人类灵长类动物的临床前研究中，我们表明抑制miR-33可以增加高密度脂蛋白-C，促进RCT和消退动脉粥样硬化斑块。这些翻译研究发现，抑制miR-33途径是一种针对高密度脂蛋白途径的新的治疗策略，特别有希望，因为它既增加了高密度脂蛋白的生物合成，又增加了胆固醇的反向转运，然而，抗miR33对高密度脂蛋白水平和功能产生有益影响的完整机制尚不清楚。因此，有一个强有力的理由对miR-33靶向通路进行全面分析，这些通路产生增加的功能性高密度脂蛋白颗粒，以促进RCT和诱导动脉粥样硬化的消退。本文提出的目标将确定miR-33途径中调节高密度脂蛋白生物发生/RCT的新角色，并确定负责抗miR33的动脉粥样硬化保护作用的靶组织。总之，这些研究将加深我们对抗miR-33途径抑制的作用机制的理解，并为这一新疗法在心脏代谢性疾病治疗中改善高密度脂蛋白功能的潜力提供重要的见解。

 DESCRIPTION (provided by applicant): Although a wealth of epidemiological studies indicate that high levels of HDL-C are associated with protection from cardiovascular disease, the recent failure of HDL-raising therapies at reducing clinical events has called the entire HDL paradigm into question. These studies underscore the critical need to better understand the mechanisms by which HDL exerts its atheroprotective effects, so that we can design therapeutics that harness these properties and provide maximum clinical benefit. Experimental studies in animals and humans indicate that therapies that increase the number of HDL particles or promote reverse cholesterol transport (RCT) confer atheroprotection. A major advance in our understanding of the regulation of HDL biogenesis and cholesterol efflux came from the identification by our lab and others those microRNA-33a/b (miR-33) represses key genes in these pathways, including ABCA1, ABCG1, NPC1. In preclinical studies in mice and non-human primates we showed that inhibition of miR-33 increases HDL-C, promotes RCT and regresses atherosclerotic plaques. These translational studies identify miR-33 pathway inhibition as a novel therapeutic strategy for targeting the HDL pathway, that is particularly promising as it increases both HDL biogenesis and reverse cholesterol transport, however the complete mechanisms by which anti-miR33 exerts its beneficial effects on HDL levels and functionality are not yet understood. There is thus a strong rationale to undertake a comprehensive analysis of miR-33 targeted pathways that generate an increased functional HDL particle to promote RCT and induce atherosclerosis regression. The aims proposed herein will identify new players in the miR-33 pathway that regulate HDL biogenesis/RCT and determine the target tissues responsible for the atheroprotective effects of anti-miR33. Together, these studies will enhance our understanding of the mechanisms of action of anti- miR-33 pathway inhibition, and provide important insight into the potential of this novel therapy for improving HDL functionality in treatment of cardiometabolic diseases.