The applicant proposes a program of research to prepare him for a career in the academic medicine. The research will be conducted in the laboratory of Dr. Joseph Bonventre at the Massachusetts General Hospital. Dr. Bonventre is an established senior investigator with an interest in acute renal failure who has successfully trained research fellows with a variety of interests. The long-term objective of the applicant is to independently investigate mechanisms of acute renal failure and improve the therapy and outcome of patients with this disease. The proximal tubule is particularly sensitive to ischemic injury and the surviving cells in this segment undergo an active process of dedifferentiation and proliferation after ischemia ultimately resulting in the reconstitution of a well differentiated polarized morphology. However the mechanisms by which the tubular epithelial cells are restored are not fully understand. Kidney Injury Molecule-1 (KIM-1) is a type 1 transmembrane protein and an epithelial cell adhesion molecule, which expresses predominantly in the injured kidney. After ischemia/reperfusion KIM-1 is coexpressed with vimentin, a marker of epithelial cell dedifferentiation. KIM-1 is also expressed in renal cell carcinoma, which state is associated with a dedifferentiated epithelial cell phenotype. The cleaved ectodomain of KIM-1 can be detected in the urine of patients with ischemic acute renal failure. In pilot experiments, we have found that tumor necrosis factor-alpha (TNF-alpha) enhanced the shedding of KIM-1 and, meanwhile, inhibitors of MEK-1, secretory phospholipase A2, and cyclooxygenase diminished the TNF-alpha induced shedding of KIM-1 in 769-P cells, which express abundant level of endogenous KIM-I under normal culture condition and constitively shed into culture media. This project's broad objectives are to define the functional role of KIM-1 and specific signaling mechanisms controlling cytokine mediated-shedding of KIM-1 in renal epithelial cells. The studies proposed in this application will provide important new insights regarding understanding functional role of KIM-1 in injury and repair of the renal tubular epithelium and may lead to new therapeutic approaches in acute diseases affecting the kidney.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
3K08DK064075-03S1
Application #
7253550
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Moen, Laura K
Project Start
2003-09-10
Project End
2008-08-31
Budget Start
2005-09-01
Budget End
2006-08-31
Support Year
3
Fiscal Year
2006
Total Cost
$1,000
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Han, Won K; Wagener, Gebhard; Zhu, Yanqing et al. (2009) Urinary biomarkers in the early detection of acute kidney injury after cardiac surgery. Clin J Am Soc Nephrol 4:873-82
Liangos, Orfeas; Tighiouart, Hocine; Perianayagam, Mary C et al. (2009) Comparative analysis of urinary biomarkers for early detection of acute kidney injury following cardiopulmonary bypass. Biomarkers 14:423-31
Han, W K; Waikar, S S; Johnson, A et al. (2008) Urinary biomarkers in the early diagnosis of acute kidney injury. Kidney Int 73:863-9
Liangos, Orfeas; Perianayagam, Mary C; Vaidya, Vishal S et al. (2007) Urinary N-acetyl-beta-(D)-glucosaminidase activity and kidney injury molecule-1 level are associated with adverse outcomes in acute renal failure. J Am Soc Nephrol 18:904-12
Han, Won K; Alinani, Anwar; Wu, Chin-Lee et al. (2005) Human kidney injury molecule-1 is a tissue and urinary tumor marker of renal cell carcinoma. J Am Soc Nephrol 16:1126-34
Han, Won K; Bonventre, Joseph V (2004) Biologic markers for the early detection of acute kidney injury. Curr Opin Crit Care 10:476-82