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

基本信息

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
项目类别：
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

项目摘要

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）：急性肾脏损伤（AKI）是一种复杂的疾病，发生率为5-10％，死亡率超过了需要透析的人的50％。氧化应激，促氧化剂和抗氧化剂之间的失衡，在介导AKI严重程度的宿主炎症反应中起关键作用。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AKI研究提供必要的技能，经验和机会，以发展为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，并从完成到完成后进行原始研究。导师和咨询委员会在AKI的临床，转化和实验室调查方面拥有丰富的经验。有几种编码促氧化酶的基因的特征良好且功能相关的单核苷酸多态性（SNP），这些酶促进了组织损伤，即NADPH氧化酶（P22Phox）和骨髓过氧化物酶（MPO），以及促进抗氧化酶修复，并促进了效果效率的效果，并在（GPX-1）。这些遗传变异可能会影响氧化应激的程度。要研究的假设是这些氧化应激相关基因中的多态性是否是AKI的预性严重程度，并且是不良临床结果的独立危险因素。具体目的是：1）表征大量AKI患者中这些促氧化和抗氧化遗传变异的频率； 2）检查它们与氧化应激的生物标志物的关系，以及肾脏疾病严重程度的措施； 3）评估这些遗传标志物是单独还是组合，预测不良临床结果，即透析需求和院内死亡率。该研究还将使用适当的TAG-SNP鉴定基因基因座中的常见单倍型。该项目是可以实现的，并有望提供新的见解，以了解遗传标记作为AKI疾病严重程度的新易感性因素的重要性。结果可能有助于鉴定可能在确定的遗传特征的基础上鉴定可能从抗氧化剂中受益的患者。公共卫生相关性：急性肾脏损伤（AKI）是肾功能突然丧失，在医院的人中通常会看到。尽管AKI通常自己会变得更好，但有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AKI的人，他们更有可能遇到更严重的肾脏和其他健康问题。