Oxidized-LDL, LOX-1 and angiogenesis

氧化 LDL、LOX-1 和血管生成

• 批准号: 8195621
• 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: 2009-10-01 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8195621
• 关键词: Address; Antibodies; Apoptosis; Area; Arterial Fatty Streak; Arteries; Arts; Atherosclerosis; Binding; Biological Assay; Blood Vessels; Blood capillaries; CD36 gene; Cell Proliferation; Cells; Cessation of life; Cholesterol; Chronic; Coronary artery; Data; Development; Diabetes Mellitus; Diabetic Retinopathy; Dyslipidemias; Embryonic Development; Endothelial Cells; Event; Extracellular Matrix Degradation; Foam Cells; Functional disorder; Generations; Genes; Growth; Growth Factor; Human; Hydrogen Peroxide; Hypertension; Inflammatory; Ischemia; Knock-out; Knockout Mice; LDL Cholesterol Lipoproteins; LOX gene; Lead; Lectin; Lesion; Low-Density Lipoproteins; Malignant Neoplasms; Mediating; Microarray Analysis; Modeling; Molecular; Molecular Biology; Mus; Myocardial Infarction; Necrosis; Oxidation-Reduction; Oxidative Stress; Oxygen; Pathogenesis; Pathologic; Physiological; Physiological Processes; Play; Process; Reactive Oxygen Species; Research; Role; Signal Transduction; Signaling Molecule; Small Interfering RNA; Smoking; Superoxides; Testing; Tissues; Training; Tube; Up-Regulation; Vascular Endothelial Growth Factors; Work; Wound Healing; angiogenesis; atherogenesis; base; capillary; cardiovascular risk factor; cell injury; cell motility; design; experience; inhibitor/antagonist; low density lipoprotein inhibitor; macrophage; matrigel; member; migration; mouse model; neovasculature; novel; oxidized LDL receptors; oxidized low density lipoprotein; preconditioning; public health relevance; receptor; research study; response; scavenger receptor; uptake

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.

概括 血管生成定义为新血管的形成，是一个生理过程 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，糖尿病性视网膜病， 以及包括动脉粥样硬化在内的慢性炎症状态。在导致的关键事件中 血管生成是活性氧（ROS）的产生，例如超氧化物阴离子和 过氧化氢在生理和病理生理状态中起关键作用。 lox-1， 凝集素样的OX-LDL受体，负责内皮中OX-LDL的结合和摄取 细胞。已经有充分的文献证明，LOX-1本身的激活可以刺激 ROS的形成并启动一系列氧化还原敏感的信号事件。我们假设 低浓度的氧化LDL（OX-LDL）激活内皮细胞中的LOX-1，诱导低浓度 ROS释放水平并启动血管生成反应。 我们在此提案中的具体目的是： 目的1：研究氧化的LDL（OX-LDL）对血管生成的影响 - 这些研究将 在人类冠状动脉内皮细胞中，在血管生成的主动脉环模型中 以及在野生型和Lox-1中敲出（KO）小鼠。 目的＃2：定义OX-LDL诱导的血管生成反应的机制 - 这些 研究将涉及许多特定抑制剂，LOX-1抗体，针对LOX-1的siRNA和 LOX-1的上调，并将涉及最新的分子生物学方法。此外，要 定义OX-LDL影响的机制，将使用微阵列技术来识别 血管生成期间上调和下调的基因。 该提案的优势是：1。PI在血管生成和 LOX-1研究。 2。PI拥有Lox-1 KO老鼠。 3。训练有素的可用性 分子生物学家在研究的大多数方面都精通。 4。PI的团队之一 成员在微阵列技术方面拥有丰富的经验。 意义：了解新生血管形成基础的理解可能会提供新颖的 基于动脉粥样硬化的信息，尤其是在不稳定病变的发展中。 从这项研究中获得的信息也可能与癌症的发展有关 这些因其生长而取决于新生血管。