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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.