Regulation of Renal Progenitor Cells in Regenerating Kidneys

描述（由申请人提供）：肾脏具有在损伤后再生的固有能力。这种修复伴随着转录因子基因如Pax 2和Lhx 1的表达，这是启动正常肾器官形成所必需的，表明再生肾小管细胞来自原始的祖细胞样状态的细胞。肾祖细胞可以在管状上皮细胞的“重编程”之后形成，例如在哺乳动物中，或者从永久驻留在肾脏中的细胞形成，例如在成年斑马鱼中。我们假设任何扩大或增强肾祖细胞的治疗都将加速急性肾损伤（阿基）后的恢复速度。为了测试这一点，我们在斑马鱼中开发了阿基的幼体和成体模型，并开发了独特的工具和方法来操纵肾祖细胞。我们进行了一项高含量筛选，以确定可增加肾祖细胞数量的化合物，并确定了一类新型组蛋白脱乙酰酶抑制剂（HDACis），当在诱导损伤后给予时，可加速斑马鱼和阿基小鼠模型的肾恢复。拟议的工作分为三个具体目标，利用两个不同机构调查人员的互补专长。目标1：我们将测试HDAC抑制是否通过诱导肾祖细胞的增殖和/或参与肾器官发生的基因的表达来加速阿基后的恢复速率。目标二：我们将通过进行功能丧失和功能获得实验来确定Pax 2/Pax 8和Lhx 1在正常肾器官形成过程中和再生反应过程中的重要性。目标3：我们将确定辅因子，包括Lhx 1转录复合物，以更好地了解如何在肾祖细胞激活肾脏程序参与这一关键因素。

DESCRIPTION (provided by applicant): The kidney has an inherent ability to regenerate following damage. This repair is concomitant with the expression of transcription factor genes such as Pax2 and Lhx1, which are essential for initiating normal kidney organogenesis, suggesting that regenerating tubular cells arise from cells with a primitive, progenitor-like state. Renal progenitors may be formed following the 're-programming' of tubular epithelial cells, such as in mammals, or from cells that permanently reside in the kidney, such as in the adult zebrafish. We hypothesize that any treatment that expands or enhances renal progenitors will accelerate the rate of recovery following acute kidney injury (AKI). To test this we developed larval and adult models of AKI in zebrafish and developed unique tools and methodologies to manipulate renal progenitors. We performed a high-content screen to identify compounds that enhance renal progenitor cell number and identified a novel class of histone deacetylase inhibitors (HDACis) that accelerates renal recovery in zebrafish and mouse models of AKI when given after the induction of injury. The proposed work is divided into three specific aims, which take advantage of the complementary expertise of investigators at two different institutions. Aim 1: We will test whether HDAC inhibition accelerates the rate of recovery following AKI by inducing the proliferation of renal progenitor cells and/or the expression of genes involved in kidney organogenesis. Aim 2: We will determine the importance of Pax2/Pax8 and Lhx1 during normal kidney organogenesis and during the regenerative response by performing loss-of-function and gain-of-function experiments. Aim 3: We wil identify cofactors that comprise the Lhx1 transcriptional complex in order to better understand how this critical factor is involved in activating a kidney program in renal progenitors.