As a physician-scientist in the field of nephrology, I have a strong interest in development and disease in the kidney. My long-term career goals are to understand cellular and molecular events in kidney development and translate this into clinically relevant therapeutics for acute kidney injury. A second goal for my career is to help elucidate the pathogenesis of heritable kidney diseases, such as polycystic diseases. Toward these goals, I have proposed a project that focuses on understanding the dynamics of cell-cell adhesion and organ morphogenesis in the developing kidney using a mouse model of polycystic disease. My research proposal, entitled "The role of p120 catenin in metanephric kidney development", is constructed to provide a framework to achieve my goals. My preliminary data shows that newborn mice lacking p120ctn in nephrons develop kidney cysts and renal hypoplasia. I have proposed three specific aims to investigate the cellular and molecular mechanisms involved. First, I will test the hypothesis that loss of p120 catenin results in polycystic kidneys due to an alteration of cellular proliferation, apoptosis or cell polarity. This will be accomplished by biochemical and histological methods in mice lacking p120 catenin from nephron precursors. Employing similar methods, I also will test the hypothesis that loss of p120 catenin results in renal hypoplasia due to reduced nephron formation resulting from a defect in mesenchymal-to-epithelial transition during development. Second, I hypothesize that p120 catenin regulates cadherin levels and additional known intracellular signaling pathways, such as Rho family GTPases and NF(B signaling. I will test this using mouse genetics, immunohistochemistry, biochemistry and quantitative PCR. Third, I hypothesize that p120 catenin may regulate novel signaling pathways in the kidney that have not yet been elucidated. I propose to perform comparative gene expression profiling using microarrays to elucidate novel signaling pathways. Together this proposal is designed to complement my prior laboratory experiences and provide me with the technical and intellectual tools to become an independent investigator.
Defining the mechanisms of p120ctn's role in kidney development is important, not only because it will help elucidate the normal mechanisms of cell adhesion and epithelial tubulogenesis, but also because it may shed light on cystic disease pathogenesis. Furthermore, identification of the molecules and pathways that underlie metanephric development may increase understanding of renal regeneration and repair and may lead to improved strategies for enhanced recovery.
|Yang, Zhufeng; Zimmerman, Susan; Brakeman, Paul R et al. (2013) De novo lumen formation and elongation in the developing nephron: a central role for afadin in apical polarity. Development 140:1774-84|
|Zacharia, Vineetha M; Manzanillo, Paolo S; Nair, Vidhya R et al. (2013) cor, a novel carbon monoxide resistance gene, is essential for Mycobacterium tuberculosis pathogenesis. MBio 4:e00721-13|
|Marciano, Denise K; Brakeman, Paul R; Lee, Chao-Zong et al. (2011) p120 catenin is required for normal renal tubulogenesis and glomerulogenesis. Development 138:2099-109|