Cytokine Gene Polymorphisms in Acute Renal Failure

急性肾衰竭中的细胞因子基因多态性

• 批准号: 7111075
• 负责人: BERTRAND L JABER
• 金额: $ 12.53万
• 依托单位: STEWARD ST. ELIZABETH'S MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-15 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7111075
• 关键词: acute renal failure; clinical research; genetic markers; genetic susceptibility; genotype; human morbidity; human mortality; human subject; interleukin 10; interleukin 6; leukocyte activation /transformation; longitudinal human study; patient oriented research; single nucleotide polymorphism; tumor necrosis factor alpha

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.

描述（由申请人提供）： 急性肾衰竭（ARF）是住院患者的严重并发症，发生率为5-10％，死亡率超过了需要透析的患者的50％。促炎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（例如细胞因子基因多态性）的重要性在很大程度上尚未得到探索。首席研究员（PI）设计了一项严格的培训计划，该计划将为他提供必要的技能，经验和机会，以发展为炎症遗传标记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的科学硕士学位，并利用广泛的研究设计进行临床研究的项目，并从成立到完成。他的导师在ARF和肾脏病临床护理研究方面具有丰富的经验。 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.这些遗传确定的差异可能会影响宿主对压力刺激的炎症反应的变化。要研究的假设是，涉及这些细胞因子预先确定ARF的严重程度的SNP是不良临床结果的独立危险因素。具体目的是：1）在一组ARF患者中，表征这些促（TNF-Alpha和IL-6）和抗炎（IL-10）细胞因子基因多态性的频率； 2）检查它们与白细胞产生和血浆细胞因子以及临床和实验室变量的关系； 3）评估这些遗传标记是单独还是组合，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，并有望提供有关遗传标记作为ARF疾病严重程度的新型易感性因素的重要性的新见解。结果可能有助于确定可能受益于抗周期疗法的患者。 PI已组建了一支科学家团队，以协助该项目进行，并召集了内部和外部科学咨询委员会，以监视其进度。拟议的培训计划和研究项目将为他做准备，使他成为独立调查员的职业。