Molecular genetic mechanisms of renal cell regeneration

点击翻译按钮获取中文摘要

PROJECT SUMMARY/ABSTRACT The goals of this project are to 1) define the functions of Pax2 and Pax8 in recovery from kidney injury and 2) provide the candidate with detailed training to facilitate an independent research career in renal regenerative medicine. How the regeneration of renal epithelia is controlled remains poorly understood. Pax2 and Pax8 are two homologous proteins that are re-expressed in regenerating renal epithelia after kidney injury, but their function in these cells is unknown. Pax2 and Pax8 also are essential for normal kidney development and can recruit histone methyltransferase complexes that can modify chromatin accessibility. Our preliminary data show that selective deletion of Pax2 and Pax8 in the proximal tubule results in decreased renal epithelial proliferation and impaired recovery after kidney injury. These observations suggest the hypothesis that Pax2 and/or Pax8 regulate regeneration by promoting de-differentiation, entry into mitosis, and the reestablishment of epigenetic marks. Our first aim is to define the steps in renal epithelial regeneration that are dysregulated by Pax2 and Pax8 deletion. Our second aim is to identify critical regeneration pathways regulated by Pax2- and/or Pax8-mediated epigenetic modifications. These studies will form an experimental framework for training the candidate in the epithelial biology of renal regeneration, epigenetics, transgenic animals, animal models of kidney injury, and bioinformatics. Training at the bench will be supplemented with didactic courses, workshops, and conferences. A mentorship team of established investigators in renal regeneration, renal physiology, and bioinformatic analysis of kidney diseases has been assembled to guide the candidate through these experiments and training activities to ensure a successful transition to independence. New expertise in the biology of renal regeneration will augment the candidate’s prior experience in clinical nephrology and biomaterials engineering to enable an independent and unique career studying renal regeneration.