Oxidative Stress Related Gene Polymorphisms in Acute kidney Injury

急性肾损伤氧化应激相关基因多态性

• 批准号: 7808021
• 负责人: MARY C PERIANAYAGAM
• 金额: $ 12.59万
• 依托单位: STEWARD ST. ELIZABETH'S MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-20 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7808021
• 关键词: 3-nitrotyrosine; Accounting; Acute; Acute Renal Failure with Renal Papillary Necrosis; Advisory Committees; Affect; Age; Antioxidants; Biological Markers; Caring; Cessation of life; Classification; Clinical; Clinical Data; Complex; Complication; Creatinine; Data; Dialysis procedure; Disease; Distress; Enzymes; Epidemiology; Equilibrium; Etiology; Frequencies; Genes; Genetic; Genetic Markers; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Variation; Haplotypes; Health; High Prevalence; Hospital Costs; Hospital Mortality; Hospitalization; Hospitals; Hypochlorous Acid; Incidence; Individual; Inflammatory Response; Injury; Interleukin-10; Investigation; Kidney; Kidney Diseases; Laboratories; Length of Stay; Measures; Mediating; Mentors; Morbidity - disease rate; NADP; Organ; Outcome; Outcome Measure; Oxidants; Oxidases; Oxidative Stress; Pathogenesis; Patients; Peroxidases; Plasma; Play; Population; Postoperative Period; Predisposition; Principal Investigator; Production; Public Health; Reactive Oxygen Species; Recruitment Activity; Regulation; Renal function; Research; Research Personnel; Resources; Risk; Risk Factors; Role; Serum; Severities; Severity of illness; Single Nucleotide Polymorphism; Site; Staging; Tissues; Training Programs; Translational Research; Tubular formation; Tumor Necrosis Factor-alpha; Whole Blood; Wound Healing; adverse outcome; base; catalase; cohort; design; epidemiology study; experience; genetic epidemiology; genetic profiling; genetic variant; glutathione peroxidase; human CYBA protein; insight; leukocyte activation; monocyte; mortality; neutrophil; novel; population based; public health relevance; skills; urinary

DESCRIPTION (provided by applicant): Acute kidney injury (AKI) is a complex disorder with an incidence of 5-10%, and mortality exceeding 50% among those who require dialysis. Oxidative stress, an imbalance between pro- and anti-oxidants, plays a pivotal role in the host inflammatory responses that mediate the severity of AKI. Yet, the importance of susceptibility genetic factors that influence the extent of oxidative stress has remained largely unexplored. The principal investigator (PI) has designed a rigorous training program that will provide the necessary skills, experience, and opportunities to develop into an independent investigator in the field of translational research and genetic epidemiology for the study of AKI. The PI will attend key didactic courses, and carry out an original research from it inception to completion. Mentors and advisory committee have extensive experience in clinical, translational and laboratory investigation of AKI. There are several well-characterized and functionally-relevant single nucleotide polymorphisms (SNPs) of genes encoding pro-oxidant enzymes that promote tissue injury, namely NADPH oxidase (p22phox) and myeloperoxidase (MPO), and anti-oxidant enzymes that promote tissue repair, namely catalase and glutathione peroxidase-1 (GPx-1). These genetic variants might influence the extent of oxidative stress. The hypotheses to be investigated are whether polymorphisms in these oxidative stress-related genes predetermine severity of AKI, and are independent risk factors for adverse clinical outcomes. The specific aims are to: 1) Characterize the frequency of these pro- and anti-oxidant genetic variants in a large cohort of patients with AKI; 2) Examine their relationship to circulating biomarkers of oxidative stress, and measures of renal disease severity; and 3) Evaluate whether these genetic markers individually or in combinations, predict adverse clinical outcomes, namely dialysis requirement and in-hospital mortality. The study will also identify common haplotypes within the gene locus using appropriate tag-SNPs. This project is achievable and promises to provide new insights into the importance of genetic markers as novel susceptibility factors for disease severity in AKI. The results may help identify patients who may benefit from anti-oxidants, on the basis of the identified genetic profiles. PUBLIC HEALTH RELEVANCE: Acute kidney injury (AKI) is a sudden loss of kidney function that is commonly seen in people who are in the hospital. Although AKI usually gets better on its own, some people are more likely to experience serious problems while in the hospital. This study will examine whether certain genes can help identify people with AKI who are more likely to experience more serious kidney and other health problems.

描述(由申请人提供)： 急性肾损伤(AKI)是一种复杂的疾病，在需要透析的人中发病率为5-10%，死亡率超过50%。氧化应激是促氧化剂和抗氧化剂之间的失衡，在宿主炎症反应中发挥着关键作用，介导了AKI的严重程度。然而，影响氧化应激程度的易感性遗传因素的重要性在很大程度上仍未被探索。首席调查员(PI)设计了严格的培训计划，将提供必要的技能、经验和机会，以发展成为AKI研究领域的翻译研究和遗传流行病学领域的独立调查员。PI将参加关键的教学课程，并从开始到完成进行原创研究。导师和咨询委员会在AKI的临床、翻译和实验室研究方面拥有丰富的经验。有几种基因的单核苷酸多态性(SNPs)编码促进组织损伤的促氧化酶，即NADPH氧化酶(P22Phox)和髓过氧化物酶(MPO)，以及促进组织修复的抗氧化酶，即过氧化氢酶和谷胱甘肽过氧化物酶-1(GPX-1)。这些基因变异可能会影响氧化应激的程度。有待研究的假设是，这些氧化应激相关基因的多态是否决定了AKI的严重程度，并且是否是不良临床结果的独立危险因素。具体目的是：1)确定这些促氧化和抗氧化基因变异在大量AKI患者中的频率；2)检查它们与氧化应激循环生物标记物以及肾脏疾病严重程度的测量之间的关系；以及3)评估这些遗传标记物是否单独或组合预测不良的临床结果，即透析需求和住院死亡率。这项研究还将使用适当的Tag-SNPs确定基因座中常见的单倍型。这个项目是可以实现的，并有望为遗传标记作为AKI疾病严重程度的新易感因素的重要性提供新的见解。根据已确定的基因图谱，这些结果可能有助于识别哪些患者可能受益于抗氧化剂。 公共卫生相关性：急性肾损伤(AKI)是一种突然的肾功能丧失，通常见于住院患者。虽然AKI通常会自行好转，但一些人在医院时更有可能遇到严重的问题。这项研究将检查某些基因是否可以帮助识别更有可能经历更严重的肾脏和其他健康问题的AKI患者。