Molecular genetic mechanisms of renal cell regeneration

项目摘要/摘要 本项目的目标是：1)明确Pax2和Pax8在肾损伤恢复中的作用；2) 为应聘者提供详细的培训，以促进肾脏再生的独立研究生涯 医药。肾上皮细胞的再生是如何被控制的仍然知之甚少。Pax2和Pax8是 两种同源蛋白在肾损伤后再生的肾上皮细胞中重新表达，但它们的 这些细胞的功能尚不清楚。Pax2和Pax8对正常的肾脏发育也是必不可少的，可以 招募可以改变染色质可及性的组蛋白甲基转移酶复合体。我们的初步数据 显示选择性缺失近端小管中的Pax2和Pax8会导致肾上皮细胞减少 肾损伤后细胞增殖和恢复受阻。这些观察结果表明，Pax2的假设 和/或Pax8通过促进去分化、进入有丝分裂和重建来调节再生 表观遗传标记。我们的第一个目标是定义肾上皮再生的步骤，这些步骤是由 Pax2和Pax8缺失。我们的第二个目标是确定由Pax2和/或 Pax8介导的表观遗传修饰。这些研究将形成一个实验框架，用于培训 肾再生上皮生物学，表观遗传学，转基因动物，动物模型 肾脏损伤和生物信息学。替补席上的训练将辅之以说教课程、讲习班、 和会议。一个由肾脏再生、肾脏生理学和 肾脏疾病的生物信息学分析已经汇集在一起，以指导候选人完成这些 进行实验和培训活动，以确保成功过渡到独立。新的专业知识 肾脏再生生物学将增强应聘者在临床肾病和肾脏病方面的经验。 生物材料工程使研究肾脏再生成为一个独立而独特的职业。

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.