The role of signaling adaptor protein epsin in atherosclerosis

项目摘要/摘要 动脉粥样硬化是威胁生命的冠心病、缺血性中风和外周疾病的主要原因 美国的动脉疾病。值得注意的是，尽管有有效的血脂，血脂异常仍然是一个主要的危险因素。 降低治疗和预防计划。这在一定程度上是由于压倒性的动脉炎症 推动从稳定的动脉粥样硬化向脆弱和易破裂的动脉粥样硬化过渡。缺乏有效的治疗方法 降低循环胆固醇，同时有力地抑制动脉粥样硬化进展过程中的炎症 为开发治疗这种毁灭性疾病的创新新药提供了机会。了解 血脂异常和动脉炎症的致病分子机制应提供 更有效的治疗方法的快速发展。我们的长期目标是发现分子 潜在的病理生理学机制和挖掘新的潜在治疗靶点。我们的大部分人 早期的研究主要集中在检测内皮细胞和血管内皮细胞中的内吞蛋白的作用 巨噬细胞调节动脉粥样硬化的进展。我们已经证明了EPSIN 1和2是 在动脉粥样硬化的小鼠模型和人类动脉粥样硬化病变中上调动脉粥样硬化斑块。 因此，内皮细胞和巨噬细胞中epsins的缺失导致显著的 动脉粥样硬化的形成。从机制上讲，我们发现epsins通过表达黏附来促进动脉炎症。 分子，促进单核细胞募集，并阻碍胞吐作用。最近，我们创造了一个肝脏- 在动脉粥样硬化小鼠模型中特异性缺乏epsins，并发现动脉粥样硬化的形成 抑制并伴有血液胆固醇水平和甘油三酯水平下降。因此，目标是 Epins、它们的结合伙伴和下游靶点是一种有吸引力的治疗方法。 解决与动脉粥样硬化发展相关的慢性血管炎症和血脂异常。在这 新的应用，我们的建议建立在令人信服的证据基础上，即Epins通过以下方式促进高脂血症 提高固醇调节元件结合蛋白(SREBP)转录活性以促进胆固醇 合成和增加低密度脂蛋白受体(LDLR)降解以扰动氧化脂质 在肝脏中清除。通过使用纳米颗粒包裹的siRNAs靶向肝脏epins，我们希望设计一种 抑制动脉粥样硬化中血脂异常的新治疗策略。我们将调查以下具体情况 目的利用独特的突变小鼠、体外模型和新型试剂：1)确定分子 肝脏内啡肽调节动脉粥样硬化SREBPs的机制，2)确定分子 在动脉粥样硬化中肝内皮质素介导的低密度脂蛋白受体下调的机制，以及3)确定 靶向肝脏内毒素对动脉粥样硬化消退的治疗潜力。如果成果丰硕，我们的发现将揭示原创 肝脏内啡肽在动脉粥样硬化高脂血症中的作用，提供了一类新的治疗策略 治疗这种疾病，并开启了与心血管疾病抗争相关研究的范式转变。

PROJECT SUMMARY/ABSTRACT Atherosclerosis is the leading cause of life-threatening coronary heart disease, ischemic stroke, and peripheral arterial disease in the United States. Notably, dyslipidemia remains a major risk factor despite effective lipid- lowering therapies and prevention programs. This is, in part, due to overwhelming arterial inflammation that drives the transition from a stable to vulnerable and rupture-prone atheroma. The lack of effective therapies to lower circulating cholesterol while forcefully curbing arterial inflammation during atheroma progression presents an opportunity to develop innovative, new medicines for this devastating disease. Understanding the causative molecular mechanisms responsible for dyslipidemia and arterial inflammation should provide for the rapid development of more potent therapeutic approaches. Our long-term goal is to uncover molecular mechanisms underlying the pathophysiology and unearth fresh potential therapeutic targets. Much of our earlier research has centered on examining the role of epsin endocytic adaptor proteins in endothelial cells and macrophages to regulate progression of atherogenesis. We have demonstrated that epsins 1 and 2 are upregulated in atherosclerotic plaques in mouse models of atherosclerosis and human atherosclerotic lesions. Consequently, deletion of epsins in the endothelium and macrophages resulted in marked attenuation of atherogenesis. Mechanistically, we showed that epsins escalate arterial inflammation by expressing adhesion molecules, enhancing monocyte recruitment, and hindering efferocytosis. More recently, we created a liver- specific deficiency of epsins in an atherosclerotic mouse model and found that atherogenesis was greatly inhibited and accompanied with diminished blood cholesterol levels and triglyceride levels. Therefore, targeting epsins, their binding partners, and downstream targets represents an attractive therapeutic approach to resolve both chronic vascular inflammation and dyslipidemia associated with atheroma development. In this new application, our proposal builds on compelling evidence that epsins contribute to hyperlipidemia by enhancing sterol regulatory element binding protein (SREBP) transcriptional activity to promote cholesterol synthesis as well as increasing low density lipoprotein receptor (LDLR) degradation to perturb oxidized lipid clearance in the liver. By targeting liver epsins using nanoparticle-encapsulated siRNAs, we hope to design a novel therapeutic strategy to impede dyslipidemia in atherosclerosis. We will investigate the following Specific Aims using unique mutant mice, in vitro models, and novel reagents: 1) to determine the molecular mechanisms by which liver epsins regulate SREBPs in atherosclerosis, 2) to determine the molecular mechanisms of liver epsin-mediated downregulation of LDLR in atherosclerosis, and 3) to determine the therapeutic potential of targeting liver epsins for atheroma resolution. If fruitful, our findings will uncover original roles for liver epsins in fueling hyperlipidemia in atherosclerosis, offer a new class of therapeutic strategies for treating this disease, and inaugurate a paradigm shift in research relevant to fighting cardiovascular disease.