LOX-1, Angiogenesis and Atherosclerosis: Search for New Therapies.

描述(由申请人提供)： 最近在我们对动脉粥样硬化形成的病理生物学的理解上的突破使我们有必要修改过于简单的好的和坏的胆固醇的概念，并为有效的治疗方法的发展提出新的方向。近年来，血管细胞氧化低密度脂蛋白(LDL)和清道夫受体依赖性氧化低密度脂蛋白(OX-LDL)被证实是导致动脉粥样硬化形成的主要因素。内皮单层是与氧化修饰的低密度脂蛋白相互作用的血管壁的主要成分。它的激活和血管生成反应是动脉粥样硬化以及斑块不稳定和最终破裂的发生和发展的先决条件。我们的研究小组已经证明，氧化低密度脂蛋白的内化主要是由凝集素样氧化低密度脂蛋白受体(LOX-1)介导的，并且氧化低密度脂蛋白介导的血管生成刺激是依赖于LOX-1的。在我们早期对高胆固醇血症小鼠模型的研究中，我们还表明，LOX-1的取消可以显著减轻动脉粥样硬化。基于这些发现，我们认为LOX-1可能成为治疗干预的一个有吸引力的靶点。为了寻找抑制ox-LDL/内皮相互作用的方法，我们利用生理上真实的ox-LDL暴露，确定了与LOX-1调控和ox-LDL下游信号有关的microRNAs。我们还筛选和鉴定了候选小分子，这些小分子基于现有的LOX-1/OX-LDL相互作用模型，显示出阻止LOX-1结合位点的潜力。我们建议进行研究，评估miRNA和基于小分子的治疗在斑块血管生成和动脉粥样硬化进展方面的作用。本研究的目的是：a)进一步阐明ox-LDL/LOX-1信号在血管生成中的作用，b)确定以LOX-1为中心的miRNA和基于小分子的干预在预防血管生成和动脉粥样硬化中的有效性。在过去的15年里，PI一直致力于LOX-1生物学的研究，他的团队对LOX-1生物学-特别是与心血管疾病有关的LOX-1生物学的阐明做出了重大贡献 在主要同行评议期刊上发表50篇论文。

DESCRIPTION (provided by applicant): Recent breakthroughs in our understanding of pathobiology of atherogenesis necessitate revision of overly simplistic concept of 'good" and "bad" cholesterol and suggest novel directions for the development of effective therapies. During the last few years, oxidation of low density lipoproteins (LDL) and scavenger-receptor dependent internalization of oxidized LDL (ox-LDL) by vascular cells was established to be a main factor driving atherogenesis. Endothelial monolayer is a primary component of vascular wall interacting with oxidatively modified LDL. Its activation and angiogenic responses are prerequisites for initiation and progression of atherosclerosis as well as plaque instability and eventual rupture. Our group has shown that ox-LDL internalization is mediated predominantly by a lectin-like ox-LDL receptor (LOX-1) and that ox-LDL mediated stimulation of angiogenesis is LOX-1 dependent. In our earlier studies in a murine model of hypercholesterolemia, we have also shown that abrogation of LOX-1 results in significant attenuation of atherosclerosis. Based on these findings we believe that LOX-1 may become an attractive target for therapeutic interventions. In search for approaches to inhibition of ox-LDL/endothelium interactions, we have determined microRNAs implicated in LOX-1 regulation and ox-LDL downstream signaling using physiologically realistic exposures to ox-LDL. We have also screened and identified candidate small molecules that, based on existing models of LOX-1/ox- LDL interactions, demonstrate a potential to block LOX-1 binding site. We propose to conduct studies that would evaluate miRNA and small molecules based therapies with regard to plaque angiogenesis and progression of atherosclerosis. The objectives of the current proposal are to: a) further elucidate the role of ox- LDL/LOX-1 signaling in relation to angiogenesis, and b) determine efficacy of LOX-1- centered miRNA and small molecule-based interventions in prevention of angiogenesis and atherosclerosis. The PI has been engaged in the research on LOX-1 biology for the last 15 years and his group significantly contributed to elucidation of LOX-1 biology - especially in relation to cardiovascular conditions - with more than 50 publications in major peer- reviewed journals.