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

• 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
• 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

 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（由适用提供）：心血管疾病（CVD）是全球死亡和疾病的主要原因，以及美国2。它占34.4个百分比 在美国的240万例死亡中，导致健康差异最大和医疗保健费用上升。众所周知，内皮功能障碍代表了CVD5计划和维护的关键步骤。尽管研究表明，包括循环炎性细胞因子，活性氧，氧化的LDL（低密度脂蛋白），自身抗体和传统危险因素的多个因素，直接和间接地导致内皮细胞功能障碍，最终导致CVD，最终导致CVD，我们对内皮细胞调节的了解仍然不足以控制这种疾病。需要更好地理解内皮细胞在生物学和病理条件下起作用的分子机制，以改善CVD的治疗。在我们先前的研究中，我们发现了一个新的分子在血管生成中尚未描述的内皮细胞中起着关键作用 - 作用于RNA1上的腺苷死亡酶（ADAR1）。该建议是定义内皮细胞中ADAR1的功能和机制。众所周知，ADAR1是转录后RNA过程的必不可少的蛋白质。它通过更改蛋白质密码子和修饰microRNA生物发生来调节基因功能。它还调节细胞质RNA信号通路，以抑制先天的免疫和应力反应。敲除ADAR1特别是在内皮细胞动态升高的血压中，在后肢缺血性动物模型中显着损害了血管生成。在这项拟议的研究中，我们将分析ADAR1的新生成的内皮特异性敲除小鼠，确定ADAR1的基因表达模式，并找到ADAR1表达与内皮细胞功能状态的潜在关联。将确定年轻健康动物，年龄和患病动物（例如糖尿病动物）的ADAR1表达水平。我们还将研究ADAR1和炎性细胞因子，活性氧，氧化的LDL的关系。我们还将通过使用后肢缺血小鼠模型来确定ADAR1在缺血状态下血管生成的作用。基于我们的初步发现，即Coviolin-1受ADAR1的调节，我们将尝试揭示ADAR1的机制，该机制调节血管功能并涉及血管疾病。