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

LOX-1，血管生成和动脉粥样硬化：寻找新疗法。

• 批准号: 8542310
• 负责人: JAWAHAR L MEHTA
• 金额: --
• 依托单位: CENTRAL ARKANSAS VETERANS HLTHCARE SYS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-09 至 2017-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8542310
• 关键词: Adhesives; Antiatherogenic; Aorta; Arterial Fatty Streak; Atherosclerosis; Attenuated; Automobile Driving; Binding Sites; Biological Assay; Biology; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell Proliferation; Cell physiology; Cells; Cholesterol; Choroidal Neovascularization; Corneal Neovascularization; Crystallography; Data; Development; Diet; Endothelial Cells; Endothelium; Exposure to; Fatty acid glycerol esters; Gene Expression; Genes; Growth; Growth and Development function; In Vitro; Intervention; Journals; Knockout Mice; LOX gene; Laboratories; Lead; Lectin; Low Density Lipoprotein oxidation; Low-Density Lipoproteins; Mediating; Methods; MicroRNAs; Modality; Modeling; Morphology; Mus; Myocardial Infarction; Pathway interactions; Peer Review; Prevention; Process; Property; Publications; RNA; Reactive Oxygen Species; Regulation; Research; Role; Rupture; Series; Signal Transduction; Stroke; Testing; Therapeutic Intervention; Toxic effect; Tube; United States; Up-Regulation; angiogenesis; artery occlusion; atherogenesis; attenuation; base; effective therapy; femoral artery; hypercholesterolemia; in vivo; inhibitor/antagonist; matrigel; monocyte; monolayer; mouse model; neovascularization; neutralizing antibody; novel; oxidized LDL receptors; oxidized low density lipoprotein; prevent; public health relevance; research study; response; scavenger receptor; small molecule; uptake

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.

描述（由申请人提供）： 在我们对动脉息护物病理生物学的理解中的最新突破需要修改过度简单的“好”和“坏”胆固醇的概念，并提出了有效疗法开发的新方向。在过去的几年中动脉粥样硬化。 OX-LDL介导的血管生成刺激是LOX-1在我们早期的高胆固醇血症模型中的研究中，我们还表明，LOX-1的废除导致动脉粥样硬化的显着衰减。根据这些发现，我们认为LOX-1可能成为治疗干预措施的有吸引力的目标。 为了寻找抑制OX-LDL/内皮相互作用的方法，我们确定了使用生理上现实的OX-LDL暴露于LOX-1调控和OX-LDL下游信号传导中的microRNA。我们还筛选并鉴定了候选小分子，这些分子基于现有的LOX-1/ox-LDL相互作用模型，证明了阻断LOX-1结合位点的潜力。 我们建议进行研究，以评估miRNA和小分子的疗法在动脉粥样硬化的血管生成和进展方面。当前建议的目的是：a）进一步阐明ox-ldl/lox-1信号在血管生成方面的作用，b）确定LOX-1中心miRNA和基于小分子的干预在预防血管生成和动脉粥样硬化方面的疗效。 在过去的15年中，PI一直从事LOX -1生物学研究，他的小组显着促进LOX -1生物学的阐明，尤其是与心血管疾病有关 主要同行评审期刊的50个出版物。