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取得的突破，需要对过于简单化的“好”和“坏”胆固醇的概念进行修正，并为有效治疗的发展提出新的方向。在过去的几年中，低密度脂蛋白（LDL）的氧化和清除剂-受体依赖性的氧化LDL（ox-LDL）的血管细胞内化被确定为驱动动脉粥样硬化形成的主要因素。 内皮细胞单层是血管壁的主要组成部分，与氧化修饰的LDL相互作用。它的激活和血管生成反应是动脉粥样硬化发生和发展以及斑块不稳定和最终破裂的先决条件。我们的小组已经表明，ox-LDL内化主要是由凝集素样ox-LDL受体（LOX-1）介导的，ox-LDL介导的血管生成刺激是LOX-1依赖性的。在我们早期对高胆固醇血症小鼠模型的研究中，我们也表明LOX-1的废除导致动脉粥样硬化的显著减弱。基于这些发现，我们认为LOX-1可能成为治疗干预的有吸引力的靶点。 在寻找抑制ox-LDL/内皮相互作用的方法中，我们已经确定了与LOX-1调节和ox-LDL下游信号转导有关的microRNA，使用生理上真实的ox-LDL暴露。我们还筛选和鉴定了候选小分子，基于现有的LOX-1/ox-LDL相互作用模型，其表现出阻断LOX-1结合位点的潜力。 我们建议进行研究，将评估miRNA和小分子为基础的治疗斑块血管生成和动脉粥样硬化的进展。本发明的目的是：a）进一步阐明ox-LDL/LOX-1信号传导在血管生成中的作用，和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功效. PI在过去的15年里一直从事LOX-1生物学的研究，他的团队对LOX-1生物学的阐明做出了重大贡献-特别是与心血管疾病相关-超过 在主要同行评审期刊上发表50篇文章。

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.