Function of a novel molecule ADAR1 in endothelial cells for angiogenesis

 描述（由申请人提供）：心血管疾病（CVD）是全球以及美国2的主要死亡和残疾原因。占34.4% 美国每年240万人死亡，导致最大的健康差距和不断上升的医疗保健成本。众所周知，内皮功能障碍是CVD启动和维持的关键步骤5。尽管研究表明多种因素，包括循环炎性细胞因子、活性氧、氧化低密度脂蛋白（LDL）、自身抗体和传统危险因素直接或间接导致内皮细胞功能障碍，并最终导致CVD，但我们对内皮细胞调节的认识仍然不足，无法开发出有效的治疗方法来控制这种疾病。需要更好地理解内皮细胞在生物学和病理学条件下发挥功能的分子机制，以改善CVD的治疗。在我们以前的研究中，我们发现了一种新的分子，它在内皮细胞的血管生成中起着关键作用，以前没有描述过--腺苷脱氨酶作用于RNA 1（ADAR 1）。本研究旨在明确ADAR 1在内皮细胞中的功能和作用机制。已知ADAR 1是RNA转录后加工的必需蛋白。它通过改变蛋白质密码子和修饰microRNA生物合成来调节基因功能。它还调节细胞质RNA信号通路以抑制先天免疫和应激反应。在后肢缺血动物模型中，特异性敲除内皮细胞中的ADAR 1显著升高血压，显著损害血管生成。在这项拟议的研究中，我们将分析新产生的内皮特异性敲除小鼠的ADAR 1，确定ADAR 1的基因表达模式，并发现ADAR 1的表达与内皮细胞的功能状态的潜在关联。将测定年轻健康动物、老年和患病动物（例如糖尿病动物）中的ADAR 1表达水平。并探讨ADAR 1与炎症细胞因子、活性氧、氧化低密度脂蛋白的关系。我们还将通过使用后肢缺血小鼠模型来确定ADAR 1在缺血条件下血管生成中的作用。基于我们对coviolin-1受ADAR 1调控的初步发现，我们将试图揭示ADAR 1调控血管功能的机制，以及ADAR 1参与血管疾病的机制。

 DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) is the leading cause of death and disabilities worldwide, as well as in the United States2. It accounts for 34.4 percent of the 2.4 million annual deaths in US, and leads to the most health disparities and rising healthcare costs. It is known that endothelial dysfunction represents a key step in the initiation and maintenance of CVD5. Although studies showed that multiple factors, including circulating inflammatory cytokines, reactive oxygen species, oxidized LDL (low density lipoprotein), autoantibodies and traditional risk factors directly and indirectly cause endothelial cell dysfunction, and eventually lead to CVD, our knowledge of endothelial cell regulation is still insufficient for the development of an effective therapeutics to control this disease. Better understanding of the molecular mechanism, by which endothelial cells functions under biological and pathologic conditions, is required to improve the treatment of CVDs. During our previous study we found a new molecule that played a critical role in endothelial cells for angiogenesis that has not be described previously -- adenosine deaminase acting on RNA1 (ADAR1). This proposal is to define the function and mechanism of ADAR1 in endothelial cells. It is known that ADAR1 is an essential protein for posttranscriptional RNA process. It regulates gene functions through changing the protein codon and modifying microRNA biogenesis. It also regulates cytoplasmic RNA signaling pathways to suppress innate immune and stress responses. Knockout ADAR1 specifically in endothelial cells dramatically elevated blood pressure, significantly impaired angiogenesis in hind limb ischemic animal models. In this proposed study, we will analyze the newly generated endothelial specific knockout mice of ADAR1, determine the gene expression pattern of ADAR1 and find the potential association of ADAR1 expression with the functional status of endothelial cells. ADAR1 expression levels in young healthy animal, aged and diseased animal, such as diabetic animals will be determined. We will also look into the relationship of ADAR1 and the inflammatory cytokines, reactive oxygen species, oxidized LDL. We will also determine the effect of ADAR1 in angiogenesis under ischemia condition by using the hind limb ischemic mouse model. Based on our preliminary finding that coviolin-1 is regulated by ADAR1, we will try to reveal the mechanism of ADAR1 by which it regulate blood vessel function and involves in blood vessel diseases.