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.
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.
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|Perianayagam, Mary C; Tighiouart, Hocine; Liangos, Orfeas et al. (2012) Polymorphisms in the myeloperoxidase gene locus are associated with acute kidney injury-related outcomes. Kidney Int 82:909-19|
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