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: 7641201
• 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/7641201
• 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; 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（阿基）是一种复杂的疾病，在需要透析的患者中发病率为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不平衡，在介导阿基严重程度的宿主炎症反应中起着关键作用。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。主要研究者（PI）设计了一个严格的培训计划，将提供必要的技能，经验和机会，发展成为阿基研究转化研究和遗传流行病学领域的独立研究者。PI将参加关键的教学课程，并从开始到完成进行原创性研究。导师和咨询委员会在阿基的临床、转化和实验室研究方面拥有丰富的经验。存在编码促进组织损伤的促氧化酶（即NADPH氧化酶（p22 phox）和髓过氧化物酶（MPO））和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））的基因的几种充分表征和功能相关的单核苷酸多态性（SNP）。这些遗传变异可能会影响氧化应激的程度。待研究的假设是这些氧化应激相关基因的多态性是否预先确定阿基的严重程度，并且是否是不良临床结局的独立风险因素。具体目标是：1）表征这些促氧化剂和抗氧化剂遗传变异体在患有阿基的大队列患者中的频率; 2）检查它们与氧化应激的循环生物标志物的关系，以及肾脏疾病严重程度的测量;以及3）评估这些遗传标志物单独或组合是否预测不良临床结果，即透析需求和住院死亡率。该研究还将使用适当的tag-SNP识别基因位点内的常见单倍型。该项目是可以实现的，并有望为遗传标记作为阿基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根据已确定的遗传特征识别可能受益于抗氧化剂的患者。 公共卫生相关性：急性肾损伤（阿基）是一种肾功能的突然丧失，常见于住院患者。虽然阿基通常会自行好转，但有些人在住院期间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出现更严重的肾脏和其他健康问题的阿基患者。