Adenosine 2A Receptor Agonist in Diabetic Nephropathy

描述(由申请人提供)： 肾脏组织内炎症通路的激活是糖尿病肾病发生发展的机制之一。激活腺苷A2a受体(A2ARs)可减轻炎症。在急性肾损伤的动物模型中，给予选择性A2AR激动剂ATL146e可以减少炎症并保护组织。在糖尿病肾病的动物模型中，A2A激动剂还可以减少炎症和蛋白尿，并防止组织学变化。目前，这种化合物正被用于第一阶段的人体研究。我们假设，给蛋白尿型糖尿病受试者服用ATL146e将减少炎症。我们的具体目的是比较静脉注射ATL146e和ACE抑制剂依那普利拉对1.尿中炎性细胞因子和生长因子浓度，2.肾总、皮质和髓质血流量及GFR的影响，3.蛋白尿。将进行一项初步研究，以确定ATL146e输注的最佳持续时间。新的超声造影(CEU)技术以及清除技术将被用于监测肾脏血流动力学的变化。CEU在心脏病学领域得到了广泛的应用，最近的研究也证明了它在肾脏病中的应用。这位候选人目前正在进行GCRC赞助的研究，使用CEU监测健康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先者的优势。候选人的乳腺导师马克·奥库萨博士在A2A激动剂的研究方面有7年的背景。联合导师尤金·巴雷特博士是糖尿病研究领域的国际知名人物，也是弗吉尼亚州国立卫生研究院赞助的GCRC的主任。这项K23课程充分利用了在临床研究、糖尿病肾脏疾病和腺苷受体的研究环境以及弗吉尼亚大学综合临床研究中心的资源方面致力于发展无止境职业的力量。资金将允许申请者接受健康评估科学、临床调查和患者导向研究方面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威廉·克瑙斯博士是候选人的顾问，他为候选人制定了具体的培训计划，并将监督他在获奖支持期间的进展。

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.