Oxidized-LDL, LOX-1 and angiogenesis

总结 血管生成是一种生理过程， 是胚胎发育和伤口修复所必需的。血管生成也是重要的 各种病理事件的组成部分，例如组织缺血，癌症，糖尿病视网膜病变， 和慢性炎症状态，包括动脉粥样硬化。在导致 血管生成是活性氧物质（ROS）如超氧阴离子的产生， 过氧化氢在生理和病理生理状态中起关键作用。LOX-1， 一种凝集素样ox-LDL受体，负责在内皮细胞中结合和摄取ox-LDL， 细胞已经有充分的文献证明LOX-1本身的激活可以刺激细胞的增殖。 ROS的形成并启动氧化还原敏感性信号传导事件的级联。我们推测 低浓度的氧化低密度脂蛋白（ox-LDL）激活内皮细胞中的LOX-1， ROS释放水平，并启动血管生成反应。 我们在这项建议中的具体目标是： 目的#1：研究氧化低密度脂蛋白（ox-LDL）对血管生成的影响-这些研究将 在人冠状动脉内皮细胞中，在血管生成的主动脉环模型中，如 以及在野生型和LOX-1敲除（KO）小鼠中。 目的#2：确定ox-LDL诱导血管生成反应的机制-这些 研究将涉及许多特异性抑制剂、LOX-1抗体、针对LOX-1的siRNA， LOX-1的上调，并将涉及最先进的分子生物学方法。进一步谈谈 为了明确ox-LDL的作用机制，将利用微阵列技术来鉴定 在血管生成过程中上调和下调的基因。 建议的优点是：1。PI具有很强的血管生成背景， LOX-1研究2. PI拥有LOX-1 KO小鼠。3.提供训练有素的 精通大部分研究领域的分子生物学家。4.私家侦探的一个团队 成员在微阵列技术方面拥有丰富经验。 意义：了解新生血管形成的基础， 动脉粥样硬化形成的基础上的信息，特别是在不稳定病变的发展。 从这项研究中获得的信息也可能与癌症的发展有关 其生长依赖于新血管系统。

Summary Angiogenesis, defined as formation of new blood vessels, is a physiological process necessary for embryonic development and wound repair. Angiogenesis is also an important component of various pathologic events such as tissue ischemia, cancer, diabetic retinopathy, and chronic inflammatory states including atherosclerosis. Among the key events leading to angiogenesis is generation of reactive oxygen species (ROS) such as superoxide anions and hydrogen peroxide which play a key role in physiological and pathophysiological states. LOX-1, a lectin-like ox-LDL receptor, is responsible for binding and uptake of ox-LDL in endothelial cells. It has been well documented that the activation of LOX-1 itself can stimulate the formation of ROS and initiate a cascade of redox-sensitive signaling events. We postulate that oxidized LDL (ox-LDL) at low concentrations activates LOX-1 in endothelial cells, induces low levels of ROS release and initiates the angiogenic response. Our specific aims in this proposal are: Aim # 1: To study the effect of oxidized LDL (ox-LDL) on angiogenesis- These studies will be done in human coronary artery endothelial cells, in an aortic ring model of angiogenesis, as well as in wild-type and LOX-1 knock out (KO) mice. Aim # 2: To define the mechanisms of ox-LDL-induced angiogenic response- These studies will involve a number of specific inhibitors, LOX-1 antibody, siRNA against LOX-1, and upregulation of LOX-1, and will involve state-of-art molecular biology approaches. Further, to define the mechanism of the effects of ox-LDL, microarray technology will be utilized to identify genes that are up-regulated and down-regulated during angiogenesis. The strengths of the proposal are: 1. The PI has strong background on angiogenesis and LOX-1 research. 2. The PI has LOX-1 KO mice in his possession. 3. Availability of well trained molecular biologist well-versed in most aspects of the research. 4. One of the PI's team members has extensive experience in microarray technology. Significance: Understanding of the basis of formation of neovasculature may provide novel information on the basis of atherogenesis, especially in the development of unstable lesions. Information gained from this study may also have relevance in the development of cancers which are dependent of neovasculature for their growth.