Adenosine 2A Receptor Agonist in Diabetic Nephropathy

描述（由申请人提供）： 肾组织内炎症通路的激活是糖尿病肾病发生的致病机制之一。腺苷 A2A 受体 (A2AR) 的激活可减少炎症。在急性肾损伤的动物模型中，施用选择性 A2AR 激动剂 ATL146e 可减少炎症并保护组织。 A2A 激动剂还可减少炎症和蛋白尿，并预防糖尿病肾病动物模型的组织学变化。目前，该化合物正用于第一阶段人体研究。我们假设给予蛋白尿糖尿病受试者的 ATL146e 会减少炎症。我们的具体目标是比较静脉注射 ATL146e 和 ACE 抑制剂依那普利拉对 1. 尿中炎症细胞因子和生长因子浓度，2. 总肾、皮质和髓质肾血流量以及 GFR 和 3. 蛋白尿的影响。将进行一项试点研究以确定 ATL146e 输注的最佳持续时间。造影增强超声（CEU）新技术以及清除技术将用于监测肾脏血流动力学变化。 CEU 已广泛应用于心脏病学领域，最近的研究也证明了其在肾脏病学领域的应用。 Tha 候选人目前正在进行 GCRC 资助的研究，使用 CEU 监测健康人类受试者局部肾血流的变化。该项目结合了弗吉尼亚大学作为腺苷 A2A 受体激动剂和糖尿病研究领域领先者的优势。候选人的主要导师 Mark Okusa 博士拥有 7 年 A2A 激动剂研究背景。联合导师尤金·巴雷特 (Eugene Barrett) 博士是糖尿病研究领域的国际知名人士，也是 NIH 资助的 UVA GCRC 主任。该 K23 利用了机构承诺的力量，以发展临床研究方面的独立职业、糖尿病肾病和腺苷受体的研究环境以及弗吉尼亚大学普通临床研究中心的资源。资金将使申请人能够接受健康评估科学、临床研究和患者方向研究领域的正式培训和硕士学位。弗吉尼亚大学公共卫生科学系主任 William Knaus 博士是该候选人的顾问，为该候选人的培训设计了具体计划，并将在资助期间监测他的进展。

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.