The primary etiologies of Chronic Kidney Disease are a direct result of initial glomerular dysfunction. Podocytes are epithelial cells in the glomerulus that help maintain the renal filtration barrier. In many glomerular diseases, the podocyte loses specific markers of differentiation, characteristic morphologic features, and the functional capacity to maintain the glomerular filtration barrier. We recently characterized the role of Kr?ppel-Like Factor 15 (KLF15), a kidney-enriched ubiquitous transcription factor, in podocyte differentiation. Specifically, we showed that a global loss of KLF15 increased the susceptibility to kidney injury in murine models of podocyte injury. Furthermore, we confirmed that the local kidney expression of KLF15 is reduced in human glomerular diseases such as FSGS and HIVAN. Finally, we also established that KLF15 is required for recovery from podocyte injury. Retinoic Acid (RA) has previously been shown to attenuate the loss of podocyte differentiation markers and thereby reduce proteinuria and ameliorate kidney disease. We have shown that RA-induced podocyte differentiation is mediated by KLF15. Glucocorticoids (GCs) are the first line of immunosuppressive therapy in the treatment of many glomerular diseases. Similar to Retinoic Acid, GCs have also been shown to protect podocytes from injury. Others have identified GC response elements in the promoter region of KLF15. We observed that dexamethasone increased KLF15 expression in human podocytes and in primary murine podocytes in culture. In addition, a loss of KLF15 in primary podocytes in culture attenuated the increase in GC-induced podocyte differentiation. Combined, we hypothesize that KLF15, a key transcriptional regulator of podocyte differentiation, mediates the renal protective effects of RA and GCs in glomerular disease. To address the hypothesis, we propose to first determine that KLF15 is necessary for podocyte differentiation using podocyte specific knockout mice and inducible, podocyte-specific KLF15 overexpression murine model. Second, we plan to ascertain the role of KLF15 in mediating renal protective effects of RA and GCs in glomerular disease. Finally, we propose to identify the upstream factors regulating KLF15 and downstream factors regulated by KLF15 in podocyte differentiation. Impact of proposed research outcome: We plan to determine whether the up-regulation of KLF15 mediates the renal protective effect of glucocorticoids and retinoic acid in glomerular disease. This will provide new insight into the podocyte biology and pathology, as well as a potential new target for therapy. Candidate's short-term and long-term goals: My short-term goal is to meet the specific aims of this research project while I continue to expand my knowledge on podocyte biology and disease by attending formal weekly divisional research conferences and monthly Work in Progress meetings. I will also attend the annual American Society of Nephrology national meeting and the biennial Podocyte meeting and FASEB KLF meeting, where I will be exposed to the latest research in the field of glomerular disease and KLF biology. I will continue to take opportunities such as these to share my data so that I can benefit in my professional development from the criticism of my colleagues in our field. Justification of the need for further training: My current research project involves the role of KLF15 in podocyte differentiation. With the K08 Award, I will be expected to expand my knowledge in molecular biology, biochemistry, and regulatory networks by attending graduate level courses at Stony Brook University School of Medicine. In addition, further mentoring from the multidisciplinary advisory committee during the next five years will be crucial in providing a strong foundation towards research independence. I am prepared to spend 75% of my professional effort towards reaching the goals outlined in my research strategy and training plan. My Long-term goal is to be an expert in KLF15 in kidney disease, specifically to gain a strong foundation in utilizing an integrative approach of molecular techniques and systems biology to identify potential therapeutic targets in glomerular disease. I can achieve this by completing the outlined training goals and the specific aims of my research strategy. In addition, as I meet my research goals, I will work on publishing my work in peer-reviewed journals and apply for foundation grants with original ideas that may stem from my current work. After four years of support from the career-development grant, I plan to begin my career as an independent investigator by applying for R01 level funding. Candidate's career development plan and environment: I have designed a multidimensional training plan to prepare me for my interdisciplinary research proposal. In addition, my mentors (Dr. Yang and Dr. He) and I have assembled multi-disciplinary panel of experts to serve on an advisory committee (Dr. Lieberthal, Dr. D'Agati, Dr. Schl?ndorff, and Dr. Ma'ayan). We have also devised a training curriculum encompassing 4 distinct modules: 1) Mastering molecular techniques to study the KLF15 signaling pathway, 2) Murine models of kidney injury and pathology, 3) Regulatory Networks in podocyte biology, and 4) Career development and grant writing skills.
Chronic Kidney Disease is predominantly a result of initial dysfunction in the glomerulus, the filtration system in the kidney, which results in proteinuria an subsequent renal failure. Injury to podocytes, epithelial cells in the glomerulus that help maintai this filtration barrier, have been implicated in many glomerular diseases and therapies targeting podocyte dysfunction have been limited. We hypothesize that Kr?ppel-like Factor 15, a novel transcriptional regulator of podocyte differentiation, mediates the renal protective effects of glucocorticoids and retinoic acid in glomerular disease.
Showing the most recent 10 out of 17 publications
