ENTPD1: A Candidate Susceptibility Gene for Renovascular Disease

ENTPD1：肾血管疾病的候选易感基因

• 批准号: 7433740
• 负责人: David J Friedman
• 金额: $ 12.66万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7433740
• 关键词: ATP Hydrolysis; Acute; Adenosine; African American; Anatomy; Apoptosis; Biological Assay; Blood Vessels; Blood flow; Cell Proliferation; Cessation of life; Chimeric Proteins; Chromosomes; Chromosomes, Human, Pair 1; Chronic; Complications of Diabetes Mellitus; Defect; Development; Diabetes Mellitus; Diabetic Nephropathy; Disease; Doctor of Medicine; Doctor of Philosophy; Early Diagnosis; End stage renal failure; Environment; Enzymes; Event; Experimental Models; Fibrosis; Genes; Genetic; Glomerular Filtration Rate; Goals; Homeostasis; Homologous Gene; Human; Hydrolysis; Hyperglycemia; Hypertension; Impairment; In Vitro; Inflammation; Injury; Insulin; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Israel; Kidney; Kidney Diseases; Kidney Failure; Knockout Mice; Laboratories; Lead; Localized; Maps; Mediating; Medical center; Medicine; Modeling; Molecular; Molecular Genetics; Mus; Mutant Strains Mice; Mutation; Nephrectomy; Non-Insulin-Dependent Diabetes Mellitus; Nucleotides; Pathologic Processes; Pathway interactions; Patients; Perfusion; Physiological; Process; Proteins; Proteinuria; Purinoceptor; Quantitative Trait Loci; Range; Rattus; Renal Blood Flow; Research; Research Personnel; Research Proposals; Rodent; Rodent Model; Role; Science; Secondary to; Series; Signal Transduction; Streptozocin; Study models; Susceptibility Gene; Thrombosis; Training; Transgenic Mice; Transgenic Organisms; Translational Research; United States; United States National Institutes of Health; Variant; angiogenesis; arteriole; career; diabetic; extracellular; glomerulosclerosis; in vivo; insulin signaling; kidney vascular structure; medical schools; migration; mouse model; mutant; nucleotide metabolism; pressure; prevent; programs; protective effect; reconstitution; research study; symposium; trait; tripolyphosphate

DESCRIPTION (provided by applicant): Diabetic nephropathy, the leading cause of renal failure in the United States, results from injury to the renal microvasculature. In this proposal, we use rodent models to investigate the protective role of ENTPD1 (also known as CD39) in renovascular disease, particularly diabetic nephropathy. ENTPD1 is a vascular ectonucleotidase that hydrolyzes ATP and ADP to AMP, thereby modulating extracellular nucleotide signaling via purinergic receptors. ENTPD1 is a protective factor in several models of acute and sub-acute vascular injury. We hypothesize that ENTPD1 is crucial in protecting the renal vasculature from chronic injury in diabetes. We also predict that the elusive mutant gene in a long-studied rat model of renal failure is ENTPD1. In Aim 1, we characterize the role of ENTPD1 in vascular protection in models of chronic vascular injury using mice null or transgenic for ENTPD1. By identifying the downstream pathways of injury driven by aberrant nucleotide signaling, we will begin to understand the mechanisms explaining ENTP1's protective effects against diabetic injury. In Aim 2, our goal is to show that reduced ENTPD1 enzymatic activity produces defects in autoregulation of renal blood flow in mouse models. Such defects are also associated with development of renal impairment in patients with diabetes. In Aim 3, we build evidence that a powerful Quantitative Trait Locus (QTL) for renal injury in rats is caused by a mutation in ENTPD1. We propose enzymatic activity assays, molecular genetics, and in vivo rescue experiments to prove this conjecture. This research will be performed predominantly at Beth Israel Deaconess Medical Center and Harvard Medical School in the lab of Simon Robson, M.D., Ph.D., a pioneer in the study of ectonucleotidases and purinergic signaling. Additional physiologic experiments will be performed by the applicant at the NIH in the laboratory of Jurgen Schnermann, M.D. The applicant's training and career development will be enhanced by coursework, conferences, seminar series, and other events in this stimulating academic environment. The applicant is a board-certified nephrologist with a passion for science and a firm commitment to translational research. This adventurous but focused research proposal and training plan will prepare the applicant for the transition to independence for a career in investigational medicine. The long-term scientific goal of this project is to understand how ENTPD1 might impact kidney disease in patients with diabetes. Our findings could eventually lead to early diagnosis and treatment of this devastating complication of diabetes.

描述（由申请人提供）： 糖尿病肾病是美国肾衰竭的主要原因，是由肾微血管损伤引起的。在本提案中，我们使用啮齿动物模型来研究 ENTPD1（也称为 CD39）在肾血管疾病，特别是糖尿病肾病中的保护作用。 ENTPD1 是一种血管核酸外切酶，可将 ATP 和 ADP 水解为 AMP，从而通过嘌呤能受体调节细胞外核苷酸信号传导。 ENTPD1 是多种急性和亚急性血管损伤模型中的保护因子。我们假设 ENTPD1 对于保护肾血管系统免受糖尿病慢性损伤至关重要。我们还预测，长期研究的大鼠肾衰竭模型中难以捉摸的突变基因是 ENTPD1。 在目标 1 中，我们使用 ENTPD1 无效或转基因小鼠，描述了 ENTPD1 在慢性血管损伤模型中血管保护中的作用。通过识别由异常核苷酸信号传导驱动的损伤的下游途径，我们将开始了解解释 ENTP1 对糖尿病损伤的保护作用的机制。在目标 2 中，我们的目标是证明 ENTPD1 酶活性降低会导致小鼠模型肾血流自动调节缺陷。这些缺陷还与糖尿病患者肾损伤的发生有关。在目标 3 中，我们建立了证据，证明大鼠肾损伤的强大数量性状基因座 (QTL) 是由 ENTPD1 突变引起的。我们提出酶活性测定、分子遗传学和体内救援实验来证明这一猜想。 这项研究将主要在贝斯以色列女执事医疗中心和哈佛医学院 Simon Robson 医学博士、哲学博士的实验室进行，他是核酸外切酶和嘌呤信号研究的先驱。申请人将在 NIH 医学博士 Jurgen Schnermann 的实验室中进行额外的生理实验。在这个激动人心的学术环境中，课程作业、会议、研讨会系列和其他活动将增强申请人的培训和职业发展。 申请人是一位经过委员会认证的肾脏病专家，对科学充满热情并坚定致力于转化研究。这项富有冒险精神但重点突出的研究计划和培训计划将为申请人过渡到独立从事研究医学职业做好准备。 该项目的长期科学目标是了解 ENTPD1 如何影响糖尿病患者的肾脏疾病。我们的研究结果最终可能导致这种破坏性糖尿病并发症的早期诊断和治疗。