Congenital anomalies of the kidney and urinary tract (CAKUT) are the primary cause of juvenile chronic kidney disease (CKD). There is no cure for CKD and progression of the disease can lead to end stage renal failure. A stronger understanding of the mechanisms that control normal kidney organogenesis will help in the design of therapeutics to treat CKD. TGF?/BMP signaling through Smads plays a pivitol role in renal fibrosis but the function of this pathway in interstitial cells during kidney development is poorly understood. Preliminary data presented in this application shows that loss of Smad4 in renal interstitial cell progenitors results in unrestricted proliferation and expansion of the medullary interstitium in postnatal mice. WNT/?-catenin drives interstitial proliferation in vivo and marker analysis shows that the loss of proliferation control observed in Smad4- deficient mice is associated with increased LEF1 expression. Therefore, Smad signaling and WNT/?- catenin/LEF1 may play opposing roles in regulating proliferation of renal interstitial cells during postnatal development. The proposed research strategy will 1) define the mechanism by which Smad4 suppresses proliferation of interstitial cells in vitro and 2) determine if BMP signaling through Smads antagonizes WNT-induced proliferation in the postnatal medullary interstitium in vivo. Through a combination of thoughtful mentoring, rigorous scientific investigation using novel methods of primary cell isolation and 3- dimensional tissue analyses, participation in technical workshops and scientific meetings, practice in manuscript and grant preparation, and an ongoing education in research ethics, the proposed training plan will prepare the applicant for a successful independent career in biomedical research.
Abnormal development of the kidneys is the leading cause of chronic kidney disease (CKD) and kidney failure in children. A greater understanding of the factors involved in normal and abnormal kidney development will help to find treatments for CKD.
