miR-33 Pathway Inhibition for Improving HDL Functionality

 描述（由申请人提供）：尽管大量流行病学研究表明高水平HDL-C与心血管疾病保护相关，但最近HDL升高治疗在减少临床事件方面的失败使整个HDL范式受到质疑。这些研究强调了更好地理解HDL发挥其动脉粥样硬化保护作用的机制的迫切需要，以便我们可以设计利用这些特性并提供最大临床益处的治疗方法。动物和人类的实验研究表明，增加HDL颗粒数量或促进胆固醇逆向转运（RCT）的治疗可提供动脉粥样硬化保护。我们对HDL生物合成和胆固醇流出调控的理解的一个重大进展来自我们实验室和其他人鉴定出的microRNA-33 a/B（miR-33）抑制这些途径中的关键基因，包括ABCA 1，ABCG 1，NPC 1。在小鼠和非人灵长类动物的临床前研究中，我们发现抑制miR-33可增加HDL-C，促进RCT并消退动脉粥样硬化斑块。这些翻译研究将miR-33途径抑制鉴定为靶向HDL途径的新型治疗策略，这是特别有前途的，因为它增加HDL生物合成和反向胆固醇转运，然而，抗miR-33对HDL水平和功能发挥其有益作用的完整机制尚未被理解。因此，对miR-33靶向途径进行全面分析是有充分理由的，这些途径产生增加的功能性HDL颗粒，以促进RCT并诱导动脉粥样硬化消退。本文提出的目的将鉴定调节HDL生物发生/RCT的miR-33途径中的新参与者，并确定负责抗miR-33的动脉粥样硬化保护作用的靶组织。总之，这些研究将增强我们对抗miR-33通路抑制作用机制的理解，并为这种新型疗法在治疗心脏代谢疾病中改善HDL功能的潜力提供重要见解。

 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.