Re-Induction of Developmental Programs during Chronic Renal Injury

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DESCRIPTION (provided by applicant): The Principal Investigator's long-term goal is to direct a basic science research program exploring the pathogenesis of kidney fibrosis. To achieve this goal he has entered a post-doctoral fellowship program, which is centered around extracellular matrix biology following his research training in renal fibroblast and tubular epithelial cell biology coupled with a clinical Nephrology clerkship at the University of Goettingen in Germany. The current postdoctoral fellowship research is conducted under supervision of Dr. Raghu Kalluri. His laboratory is well suited to provide guidance in established and new molecular techniques and transgenic animal studies to foster the start of an independent career. The research project proposed here centers on exploring endogenus regenerative mechanisms, which facilitate protection from kidney injury and its use in designing therapies to protect the kidney from chronic progressive kidney disease. The central hypothesis of this proposal is that the recovery from renal injury follows pathways, which are similar to those, which mediate kidney development. Such thinking is based on previous studies, which demonstrate that administration of bone morphogenic protein-7 (BMP-7), a growth factor involved in tubulogenesis during kidney development, facilitates regression of chronic kidney disease. These previous studies suggest that BMP-7 may reverse epithelial to mesenchymal transition (EMT) involving injured tubular epithelial cells, leading to accumulation of fibroblasts. Additionally, BMP-7 also induces phenotypic changes in medullary renal fibroblasts resembling mesenchymal to epithelial transition, regenrating epithelial cells. The study aims proposed in this application are centered around testing the potential role of fibroblasts in the repair of renal injury and they attempt to further analyze the preliminary phenotypic observation at a molecular level.