Kidney Injury Molecule-1 in Renal Fibrosis

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This proposal describes a 5 year training program for the continued development of a career in academic nephrology. The principal investigator has completed residency and clinical nephrology training in Boston and now will expand his scientific skills through a carefully formulated plan combining the unique resources of Brigham and Women's Hospital and Harvard University. The plan will promote command of epithelial cell biology as it relates to renal injury and fibrosis. The principal investigator's scientific development will be fostered by Dr. Joseph Bonventre, the Chief of the Division of Nephrology. To enhance training, this proposal includes a collaboration with Dr. Andrew McMahon, an expert in the cellular and molecular mechanisms which regulate growth and differentiation. In addition, an advisory committee will provide scientific advice and career guidance. The committee includes Dr. Dennis Brown, a renal epithelial cell biologist and expert microscopist, Dr. Raghu Kalluri, an extracellular matrix biologist and Dr. Arlene Sharpe, an immunologist and Director of the mouse transgenic core facility. Research will focus on Kidney Injury Molecule-1 (Kim-1), a membrane protein identified by Dr. Bonventre's lab that is strongly induced in proximal tubular renal epithelium after kidney injury.Kim-1 promotes a dedifferentiated cell phenotype in vitro, and we hypothesize that Kim-1aids in tubular regeneration after injury by promoting cellular dedifferentiation and proliferation leading to regeneration of an intact tubular epithelium. Aberrant or chronic expression of this protein, however, may drive epithelial to mesenchymal transition (EMT)and ultimately cause renal fibrosis. The specific aims of this proposal include: 1) Characterize Kim-1 dependent EMT and signaling pathways using cell culture models, 2) Identify proteins that interact with the cytoplasmic domain of Kim-1using the yeast two-hybrid technique and 3) Create a mouse model with targeted overexpression of Kim-1 in renal proximal tubules to determine whether chronic overexpression of Kim-1 promotes renal fibrosis. The increasing prevalence of chronic kidney disease in our aging population represents an enormous health burden. Because the final common pathway for chronic nephropathies is renal fibrosis, therapies that reverse or slow fibrosis would have tremendous clinical impact. These studies could validate Kim-1 as a therapeutic target in renal fibrosis and are therefore of great public health interest.