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

尿酸作为 CKD 患者内皮功能障碍的介质

• 批准号: 8137219
• 负责人: Diana I Jalal
• 金额: $ 17.94万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-15 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8137219
• 关键词: 3-nitrotyrosine; Acids; Adhesions; Age-Years; Albuminuria; Allopurinol; Arteries; Atherosclerosis; Award; Biochemical; C-reactive protein; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Chronic Kidney Failure; Clinical; Clinical Research; Clinical Trials; Collaborations; Colorado; Complex; Data; Development; Dietary Factors; Disease Progression; Diuretics; Doctor' s Degree; Dose; Double-Blind Method; Endothelial Cells; Endothelium; Enrollment; Environment; Enzymes; Etiology; Event; Fostering; Foundations; Functional disorder; Future; Grant; Health Sciences; Human; Immunofluorescence Immunologic; Immunohistochemistry; In Vitro; Incidence; Individual; Inflammation; Inflammation Mediators; Inflammatory; Injury; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Intercellular adhesion molecule 1; Interleukin-6; Kidney; LDL Cholesterol Lipoproteins; Laboratories; Lead; Link; Measurement; Measures; Mediating; Mediator of activation protein; Mentors; Monocyte Chemoattractant Protein-1; N,N-dimethylarginine; NADP; Nuclear; Outcome; Oxidases; Oxidative Stress; Pathway interactions; Patients; Phenotype; Placebos; Plasma; Play; Population; Positioning Attribute; Proteins; Publications; Publishing; Randomized; Randomized Clinical Trials; Randomized Controlled Clinical Trials; Recovery; Research Personnel; Role; Serum; Staging; Staining method; Stains; Techniques; Testing; Training; Translational Research; Universities; Uric Acid; Vascular resistance; Venous; Work; Xanthine Oxidase; brachial artery; cardiovascular disorder risk; cardiovascular risk factor; career; experience; high risk; human NOS3 protein; improved; inflammatory marker; isoprostaglandin F2alpha type-III; kidney vascular structure; mortality; oxidized low density lipoprotein; p65; patient population; professor; prospective; protein expression; public health relevance; skills; symposium; xanthine oxidase inhibitor

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.

描述（由申请人提供）：本提案的目的是培养候选人 Jalal 博士的科学发展和实验室技能，使她成为一名能够进行临床转化研究的独立研究者。肾脏科与科罗拉多大学丹佛分校的临床和转化研究中心合作，为 Jalal 博士提供最佳环境，以在临床、生化和细胞水平上检查降低血清尿酸水平对中度慢性肾病 (CKD) 患者内皮功能的影响。 Jalal 博士目前担任科罗拉多大学丹佛健康科学中心的助理教授。通过她的主要导师约翰逊博士以及由经验丰富的科学和临床研究人员组成的广泛网络，贾拉尔博士将为独立学术生涯的发展奠定基础。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患者出现高尿酸血症。尿酸与内皮功能障碍的病因有关。实验证据表明它通过炎症和氧化应激介导其对脉管系统的下游影响。我们假设尿酸会诱发氧化应激和炎症，并导致同时患有高尿酸血症的 III 期 CKD 患者的内皮功能障碍。 Jalal 博士在她的资助中提出了一项随机对照临床试验，其中 80 名 III 期 CKD 且血清尿酸水平 > 7mg/dL 的患者将随机接受安慰剂或别嘌呤醇治疗 3 个月。该提案的具体目标包括：1. 通过测量肱动脉血流介导的扩张，确定降低血清尿酸可改善内皮依赖性扩张；2. 确定降低血清尿酸水平将减轻全身炎症和氧化应激；3. 通过免疫荧光确定降低血清尿酸水平将抑制炎症和氧化途径的内皮细胞激活。对于每个具体目标，将在基线和研究期结束时获得测量结果，并将随机接受别嘌呤醇的组和随机接受安慰剂的组之间相对于基线的变化进行对比。这项研究的结果将回答一个重要的临床问题，并将产生可发表的作品。此外，该试验的结果可能为更大规模的临床试验奠定基础，以评估降尿酸疗法对轻中度 CKD 患者心血管事件和 CKD 进展的影响。 公共健康相关性：我们提出一项临床试验来检验这一假设：对于同时患有高尿酸血症的 III 期 CKD 患者，使用黄嘌呤氧化酶抑制剂（别嘌呤醇）降低血清尿酸水平将改善临床、生化和细胞水平的内皮功能、炎症和氧化应激。该应用程序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分校的肾脏科处于有利地位，可以帮助候选人完成拟议的研究。该奖项将允许进行正式课程工作以获得临床研究博士学位、发表论文和参加国家会议以及建立合作关系。此外，它将对候选者进行内皮细胞恢复和蛋白质表达方面的教育，这项技术可以在未来的其他研究中使用。拟议的研究将产生可发表的结果，并可能导致更大规模的临床试验，旨在评估降尿酸药物对 CKD 患者预后的影响。