Function of a novel molecule ADAR1 in endothelial cells for angiogenesis

内皮细胞中新分子 ADAR1 的血管生成功能

基本信息

批准号：
9093016
负责人：
Qingde Wang
金额：
$ 19.17万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-15 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9093016
关键词：
Accounting Adenosine Adult Affect Aging Animal Model Animals Autoantibodies Biogenesis Biological Blood Blood Pressure Blood Vessels Cadherins Cardiovascular Diseases Cardiovascular system Cause of Death Cell Differentiation process Cell Proliferation Cell physiology Cessation of life Codon Nucleotides Coronary Arteriosclerosis Data Defect Development Disease Double-Stranded RNA Embryo Endothelial Cells Exhibits Functional disorder Gene Expression Profile Generations Goals Health Care Costs Hematopoiesis Immune response Inflammatory Inosine Ischemia Knock-out Knockout Mice Knowledge Lead Life Limb structure Maintenance Messenger RNA MicroRNAs Modeling Molecular Mus Myocardial Infarction Pathogenesis Pathologic Pathology Pathway interactions Pattern Physiological Physiology Play Post-Transcriptional RNA Processing Prevention Proteins Publications RNA RNA Editing RNA I RNA Splicing Reactive Oxygen Species Regulation Reperfusion Therapy Risk Factors Role Signal Pathway Signal Transduction Site Solid Stress Stroke Therapeutic Tissues Transgenes Work adenosine deaminase aged angiogenesis base biological adaptation to stress blood vessel development cytokine diabetic disability disorder control endothelial dysfunction functional status gene function health disparity improved knockout gene mouse model novel outcome forecast oxidized low density lipoprotein promoter public health relevance

项目摘要

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.

描述（由申请人提供）：心血管疾病 (CVD) 是全世界死亡和残疾的主要原因，在美国也占 34.4%2。美国每年有 240 万人死亡，并导致最大的健康差异和医疗费用上升。众所周知，内皮功能障碍是 CVD 发生和维持的关键步骤5。、活性氧、氧化LDL（低密度脂蛋白）、自身抗体以及传统危险因素直接和间接导致内皮细胞功能障碍，并最终导致CVD，我们对内皮细胞调节的认识是仍然不足以开发出有效的治疗方法来控制这种疾病，需要更好地了解内皮细胞在生物和病理条件下发挥作用的分子机制，以改善心血管疾病的治疗。在内皮细胞的血管生成中发挥着先前未曾描述过的关键作用——作用于RNA1 (ADAR1)的腺苷脱氨酶。该提案旨在定义ADAR1在内皮细胞中的功能和机制。众所周知，ADAR1 是转录后 RNA 过程的必需蛋白，它通过改变蛋白质密码子和修饰 microRNA 生物发生来调节基因功能，还可以调节细胞质 RNA 信号通路，从而显着抑制内皮细胞中的先天免疫和应激反应。血压升高，后肢缺血动物模型中血管生成显着受损。在这项拟议的研究中，我们将分析新生成的 ADAR1 内皮特异性敲除小鼠，确定基因表达。我们还将研究 ADAR1 和 ADAR1 的关系，并发现 ADAR1 表达与年轻健康动物、老年和患病动物（例如糖尿病动物）中 ADAR1 表达水平的潜在关联。根据我们的初步发现，我们还将通过使用后肢缺血小鼠模型来确定 ADAR1 在缺血条件下血管生成中的作用。 coviolin-1受ADAR1调节，我们将尝试揭示ADAR1调节血管功能并参与血管疾病的机制。