Adenosine 2A Receptor Agonist in Diabetic Nephropathy

腺苷 2A 受体激动剂治疗糖尿病肾病

基本信息

批准号：
8111822
负责人：
KAMBIZ KALANTARI
金额：
$ 13.08万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8111822
关键词：
ATL 146e Acids Acute Address Adenosine Age Agonist Albuminuria Angiotensin-Converting Enzyme Inhibitors Animal Model Animals Anti-Inflammatory Agents Anti-inflammatory Award Blood flow Bone Marrow CCL2 gene Cardiology Cells Chronic Clinical Research Clinical Trials Complex Complications of Diabetes Mellitus Control Groups Creatinine Crossover Design Development Diabetes Mellitus Diabetic Nephropathy Diagnosis Disease Progression Dose Enalaprilat End stage renal failure Endotoxins Environment Evaluation Excretory function Exposure to Filtration Foundations Funding Future Gender Glomerular Filtration Rate Growth Factor Health Health Sciences Human Incidence Individual Inflammation Inflammatory Infusion procedures Injury Interleukin-1 Interleukin-10 Interleukin-18 Interleukin-6 Intervention Studies Intravenous Iothalamate Kidney Kidney Diseases Lead Master&apos s Degree Measures Mentors Methods Microbubbles Modeling Monitor Morbidity - disease rate Names Nephrology Pathogenesis Pathway interactions Pharmaceutical Preparations Phase Phase I Clinical Trials Pilot Projects Plasma Play Population Study Property Proteins Proteinuria Public Health Purinergic P1 Receptors RANTES Race Randomized Reducing Agents Renal Blood Flow Renin-Angiotensin System Reperfusion Injury Reporting Research Research Personnel Resources Role Safety Science Serum Stretching TNF gene Techniques Testing Therapeutic Tissues Training Translating Ultrasonography United States National Institutes of Health Universities Urine Virginia age group arteriole base career cytokine design diabetic diabetic patient glomerulosclerosis healthy volunteer hemodynamics human subject industry partner inflammatory marker macrophage mesangial cell mortality novel patient oriented preclinical study prevent programs receptor response standard of care urinary

项目摘要

DESCRIPTION (provided by applicant): Activation of inflammatory pathways within the kidney tissue is one of the pathogenic mechanisms in the development of diabetic nephropathy. Activation of adenosine A2A receptors (A2ARs) reduces inflammation. In animal models of acute renal injury, administration of ATL146e, a selective A2AR agonist, reduces inflammation and protects tissue. A2A agonists also reduce inflammation and proteinuria and prevented histological changes in an animal model of diabetic nephropathy. Currently, this compound is being used in phase I human studies. We hypothesized that ATL146e given to proteinuric diabetic subjects will reduce inflammation. Our specific aims are to compare the effects of intravenous ATL146e and ACE inhibitor, enalprilat, on, 1. urinary concentration of inflammatory cytokines and growth factors, 2. total, cortical and medullary renal blood flows and GFR and 3. Proteinuria. A pilot study will be done to determine the optimum duration of ATL146e infusion. Novel technique of contrast enhanced ultrasound (CEU) as well clearance techniques will be used to monitor renal hemodynamic changes. CEU has been used extensively in the field of cardiology and recent studies have demonstrated applications for its use in nephrology as well. Tha candidate is currently conducting GCRC-sponsored study using CEU in monitoring changes in regional renal blood flow in healthy human subjects. This project combines the strengths of the University of Virginia as a leader in both the study of adenosine A2A receptor agonist and diabetes. Dr Mark Okusa, candidate's promary mentor, has 7 years of background in research on A2A agonist. Dr. Eugene Barrett, the co-mentor, is an internationally recognized name in the field of diabetes research and the Director of the NIH- sponsored GCRC at UVA. This K23 leverages the strength of the insitutional commitment toward deveveloping indendent careers in clinical investigation, the research environment in diabetic kidney disease and adenosine receptors, and the resources of the General Clinical Research Center at the Unvirsity of Virginia. Funding will permit the applicant to receive formal training and a masters degree in Health Evaluation Sciences, Clinical Investigation and Patient Orients Researcg track. Dr William Knaus, the director of the Department of Public Health Sciences at UVA, is an advisor to the candidate and has designed a specific plan for the candidate's training and will monitor his progress during the years of award support.

描述（由申请人提供）：肾脏组织内炎症途径的激活是糖尿病肾病发展中的致病机制之一。腺苷A2A受体（A2AR）的激活减少炎症。在急性肾脏损伤的动物模型中，一种选择性A2AR激动剂ATL146E的给药可减少炎症并保护组织。 A2A激动剂还减少炎症和蛋白尿，并阻止糖尿病肾病动物模型的组织学变化。目前，该化合物已用于I期人类研究。我们假设给予蛋白尿糖尿病患者的ATL146E将减少炎症。我们的具体目的是比较静脉注射ATL146E和ACE抑制剂的作用，Enalprilat，1。炎症细胞因子和生长因子的尿液浓度，2。总，皮质和髓质血液流量和髓质血液流量和GFR和GFR和3。蛋白尿。将进行一项试点研究，以确定ATL146E输注的最佳持续时间。对比度增强超声（CEU）的新型技术以及清除技术将用于监测肾脏血液动力学变化。 CEU已在心脏病学领域广泛使用，最近的研究也证明了其在肾脏病中的应用。 THA候选人目前正在使用CEU进行GCRC赞助的研究，以监测健康人类受试者的区域肾脏血流的变化。该项目结合了弗吉尼亚大学的优势，成为腺苷A2A受体激动剂和糖尿病研究的领导者。候选人的招聘导师Mark Okusa博士在A2A激动剂研究方面拥有7年的背景。院长尤金·巴雷特（Eugene Barrett）博士是糖尿病研究领域的国际公认名称，也是UVA的NIHSPONSED GCRC主任。该K23利用了对临床研究中的沉迷职业，糖尿病肾脏疾病和腺苷受体的研究环境以及在弗吉尼亚州婚姻中的一般临床研究中心的资源的实力。资金将允许申请人获得正规培训和健康评估科学，临床调查和患者外观研究的硕士学位。 UVA公共卫生科学系主任William Knaus博士是候选人的顾问，并为候选人的培训设计了一项特定计划，并将在奖励支持年度监视其进度。