Cytokine Gene Polymorphisms in Acute Renal Failure

描述（由申请人提供）： 急性肾功能衰竭（ARF）是住院患者的严重并发症，发病率为5- 10%，需要透析的患者死亡率超过50%。促炎细胞因子和抗炎细胞因子在介导ARF严重程度的宿主炎症反应中起关键作用。然而，易感性遗传因素如细胞因子基因多态性的重要性仍然在很大程度上未被探索。主要研究者（PI）设计了一个严格的培训计划，将为他提供必要的技能，经验和机会，发展成为炎症遗传标志物和急性肾衰竭流行病学领域的独立研究者。他将获得临床护理研究理学硕士学位，参与利用广泛的临床研究设计的项目，并从开始到完成进行原创研究项目。他的导师在ARF的临床和实验室研究以及肾脏病学的临床护理研究方面具有丰富的经验。 人肿瘤坏死因子-α（TNF-α）（位置-308）、白细胞介素-6（IL-6）（位置-174）和白细胞介素-10（IL-10）（位置-1082）基因的启动子区域中的单核苷酸多态性（SNP）影响转录活性并具有功能相关性。这些基因决定的差异可能会影响宿主对应激刺激的炎症反应的变化。有待研究的假设是涉及这些细胞因子的SNP预先确定ARF的严重程度，并且是不良临床结局的独立危险因素。具体目标是：1）表征这些亲的频率，（TNF-α和IL-6）和抗炎（IL-10）细胞因子基因多态性; 2）检查它们与白细胞产生和血浆细胞因子水平以及临床和实验室变量的关系;和3）评估这些遗传标记单独或组合是否预测不良临床结果，主要是透析需求和死亡率。该研究项目是可以实现的，并有望为遗传标记作为ARF疾病严重程度的新易感因素的重要性提供新的见解。这些结果可能有助于确定可能受益于抗细胞因子治疗的目标患者。 PI已组建了一个科学家团队，以协助开展该项目，并召集了内部和外部科学咨询委员会，以监测其进展情况。拟议的培训计划和研究项目将为他作为独立调查员的职业生涯做好准备。

DESCRIPTION (provided by applicant): Acute renal failure (ARF) is a serious complication in hospitalized patients, with an incidence of 5-10%, and mortality exceeding 50% among those who require dialysis. Pro- and anti-inflammatory cytokines play a pivotal role in the host inflammatory responses that mediate the severity of ARF. Yet, the importance of susceptibility genetic factors such as cytokine gene polymorphisms has remained largely unexplored. The principal investigator (PI) has designed a rigorous training program that will provide him with the necessary skills, experience, and opportunities to develop into an independent investigator in the field of inflammatory genetic markers and epidemiology of acute renal failure. He will obtain a Masters of Science in Clinical Care Research, participate in projects utilizing a broad range of study designs for clinical research, and carry out an original research project from its inception to completion. His mentors have extensive experience in clinical and laboratory investigation of ARF and clinical care research in Nephrology. Single nucleotide polymorphisms (SNP) in the promoter region of the human tumor necrosis factor-alpha (TNF-alpha) (position -308), interleukin-6 (IL-6) (position -174) and interleukin-10 (IL-10) (position -1082) genes affect transcriptional activity and have functional relevance. These genetically determined differences might influence variations in host inflammatory responses to stressful stimuli. The hypotheses to be investigated are that SNP involving these cytokines predetermine the severity of ARF, and are independent risk factors for adverse clinical outcomes. The specific aims are to: 1) characterize the frequency of these pro- (TNF-alpha and IL-6) and anti-inflammatory (IL-10) cytokine gene polymorphisms in a cohort of patients with ARF; 2) Examine their relationship to leukocyte production and plasma levels of cytokines as well as clinical and laboratory variables; and 3) Evaluate whether these genetic markers individually or in combinations, predict adverse clinical outcomes, mainly dialysis requirement and mortality. The research project is achievable and promises to provide new insights into the importance of genetic markers as novel susceptibility factors for severity of disease in ARF. The results may help identify target patients who may benefit from anti-cytokine therapies. The PI has assembled a team of scientists to assist in the conduct of the project, and convened and internal and external scientific advisory committee to monitor his progress. The proposed training program and research project will prepare him for a career as an independent investigator.