Uric Acid as a Mediator of Endothelial Dysfunction in Patients with CKD

描述(申请人提供)：这项建议的目的是培养候选人Jalal博士的科学发展和实验室技能，使她可以成为一名独立的研究员，可以进行临床翻译研究。肾脏科与科罗拉多大学丹佛分校的临床和翻译研究中心合作，能够为Jalal博士提供最佳环境，以检查降低血尿酸水平对中度慢性肾脏疾病(CKD)患者的临床、生化和细胞水平的内皮功能的影响。贾拉尔博士目前在科罗拉多大学丹佛健康科学中心担任助理教授。通过她的主要导师约翰逊博士，以及一个由经验丰富的科学和临床研究人员组成的广泛网络，贾拉尔博士将获得独立学术生涯发展的基础。内皮功能障碍、炎症和氧化应激在CKD患者中普遍存在，并在动脉粥样硬化和CKD进展中发挥核心作用。由于多种因素的影响，CKD患者存在高尿酸血症。尿酸与内皮功能障碍的病因学有关。实验证据表明，它通过炎症和氧化应激调节其对血管系统的下游影响。我们假设尿酸诱导氧化应激和炎症，并导致高尿酸血症的III期CKD患者的内皮功能障碍。在她的资助中，Jalal博士提出了一项随机对照临床试验，将80名CKD III期且血尿酸水平为7 mg/dL的患者随机分为安慰剂或别嘌醇治疗3个月。该提案的具体目的包括：1.通过测量肱动脉血流介导的扩张来确定降低血尿酸水平改善内皮依赖性扩张；2.确定降低血尿酸水平将缓解全身炎症和氧化应激；3.通过免疫荧光确定降低血尿酸水平将抑制炎症和氧化途径中内皮细胞的激活。对于这些特定目标中的每一个，将在基线和研究结束时进行测量，并在随机服用别嘌醇组和随机服用安慰剂组之间对比基线的变化。这项研究的结果将回答一个重要的临床问题，并将导致发表的工作。此外，这项试验的结果可能会为更大规模的临床试验奠定基础，以评估降低尿酸疗法对轻中度CKD患者心血管事件和CKD进展的影响。 公共卫生相关性：我们正在提议进行一项临床试验，以验证这样一种假设，即使用黄嘌呤氧化酶抑制剂(别嘌醇)降低血尿酸水平将在临床、生化和细胞水平上改善临床、生化和细胞水平的内皮功能、炎症和氧化应激。这一申请为临床研究培训提供了理想的工具，因为科罗拉多大学丹佛大学的肾科处于有利地位，能够使候选人完成拟议的研究。这一奖项将允许正式的课程工作，以获得临床研究、出版和参与国家会议的博士学位，并建立合作关系。此外，它还将培训候选人在内皮细胞恢复和蛋白质表达方面的知识，这项技术可以在未来的其他研究中使用。这项拟议的研究将导致可发表的结果，并可能导致更大规模的临床试验，旨在评估尿酸降低剂对慢性肾脏病患者预后的影响。

DESCRIPTION (provided by applicant): The purpose of this proposal is to foster the scientific development and laboratory skills of the candidate, Dr. Jalal, so that she may become an independent investigator, who can perform clinical translation research. The Renal Division in collaboration with the Clinical and Translation Research Center at the University of Colorado Denver are in a position to provide Dr. Jalal with the optimal environment to examine the impact of lowering serum uric acid levels on endothelial function, at the clinical, biochemical, and cellular level, in patients with moderate chronic kidney disease (CKD). Dr. Jalal is currently as assistant professor at the University of Colorado at Denver Health Sciences Center. Through her primary mentor, Dr. Johnson, and an extensive network of experienced scientific and clinical researchers, Dr. Jalal will obtain the foundation for the development of an independent academic career. Endothelial dysfunction, inflammation, and oxidative stress are prevalent in patients with CKD, and play a central role in atherosclerosis and in CKD progression. Due to a variety of factors, patients with CKD are hyperuricemic. Uric acid has been implicated in the etiology of endothelial dysfunction. Experimental evidence suggests it mediates its downstream effects on the vasculature via inflammation and oxidative stress. We hypothesize that uric acid induces oxidative stress and inflammation, and contributes to endothelial dysfunction in patients with stage III CKD who are also hyperuricemic. In her grant, Dr. Jalal proposes a randomized controlled clinical trial, where 80 patients with stage III CKD and serum uric acid levels acid > 7mg/dL will be randomized to either placebo or allopurinol for 3 months. The specific aims of the proposal include: 1. determine of lowering serum uric acid improves endothelial dependant dilation by measuring brachial artery flow mediated dilation, 2. determine that lowering serum uric acid levels will mitigate systemic inflammation and oxidative stress, and 3. determine that lowering serum uric acid levels will curb endothelial cellular activation of inflammatory and oxidative pathways by immunofluorescence. For each of these specific aims, measurements will be obtained at baseline and the end of the study period, and changes from baseline will be contrasted between the group randomized to allopurinol and the group randomized to placebo. The results of this study will answer an important clinical question, and will result in publishable work. In addition, the findings of this trial will likely set the stage for larger clinical trials to evaluate the impact of uric acid lowering therapies on cardiovascular events and CKD progression in patients with mild- moderate CKD. PUBLIC HEALTH RELEVANCE: We are proposing a clinical trial to test that hypothesis that lowering serum uric acid levels with a xanthine oxidase inhibitor (allopurinol) will improve endothelial function, inflammation, and oxidative stress at the clinical, biochemical, and cellular level, in patients with stage III CKD who are also hyperuricemic. This application presents an ideal vehicle for training in clinical research, as the Renal Division at the University of Colorado Denver is in a strong position to enable the candidate to complete the proposed study. This award will allow for formal course work to obtain a doctorate degree in clinical research, publications and participation in national conferences, and the establishment of collaborative relationships. In addition, it will educate the candidate in endothelial cell recovery and protein expression, a technique that can be utilized in other studies in the future. The proposed study will result in publishable findings, and may lead to larger clinical trials aimed to evaluate the impact of uric acid lowering agents on outcomes in patients with CKD.