Genetic Regulation of Nephron Progenitor Cells in the Mammalian Kidney

描述（由申请人提供）：肾脏的基本功能单位，肾元，在肾脏器官发生过程中反复产生。肾脏疾病时，肾单位丢失，纤维化间质扩张。虽然哺乳动物肾脏可以再生部分受损的肾单位，但没有观察到肾单位的新生形成。在肾脏发育过程中，我们先前确定帽间质是一个多能自我更新的肾细胞祖细胞群。我们的初步数据表明肾元和间质形成不同的室室，具有不同的谱系边界。目前还不清楚肾单位和间质组织是如何被指定和维持的。我们的初步数据表明，在肾脏器官发生过程中，转录因子PAX2通过抑制向间质的反式分化来维持肾元祖细胞是必不可少的。因此，Pax2活性在肾脏器官发生过程中建立了肾元和间质谱系之间的发育界限。然而，Pax2活性如何维持肾元祖细胞尚不清楚。此外，尽管我们的数据表明Pax2是维持肾元祖细胞所必需的，但Pax2活性是否足以确定肾元祖细胞的状态尚不清楚。本研究拟进一步探讨Pax2基因在肾元发育过程中的作用。在Aim 1中，我们将对肾元祖细胞的Pax2功能进行详细的分子分析。在Aim 2中，我们将研究Pax2是否调节细胞粘附以维持帽间质细胞。在Aim 3中，我们将比较肾元分化开始前后Pax2的功能。我们提出的研究将更好地了解肾元祖细胞的遗传调控机制，这可能会导致人类肾脏疾病的新治疗模式的发展。

DESCRIPTION (provided by applicant): The basic functional unit of the kidney, the nephron, is generated repetitively during kidney organogenesis. With kidney disease, nephrons are lost and the fibrotic interstitium expands. Although the mammalian kidney can regenerate partially-damaged nephrons, de novo formation of nephrons is not observed. During kidney development, we previously identified the cap mesenchyme as a multipotent self-renewing nephron progenitor population. Our preliminary data suggest that nephron and interstitium form distinct compartments with a distinct lineage boundary. Currently it is unclear how the nephron and interstitial tissues are specified and maintained. Our preliminary data suggest that a transcription factor PAX2 is essential to maintain nephron progenitor cells by repressing trans-differentiation into the interstitium during kidney organogenesis. Thus, Pax2 activity establishes the developmental boundary between the nephron and interstitial lineages during kidney organogenesis. However, how Pax2 activity maintains nephron progenitor cells is unknown. Furthermore, although our data suggest that Pax2 is required to maintain nephron progenitor cells, it remains unclear whether Pax2 activity is sufficient to specify the nephron progenitor status. In this study, we propose to further investigate roles of the Pax2 gene during nephron development. In Aim 1, we will perform detailed molecular analysis of Pax2 functions for nephron progenitor cells. In Aim 2, we will examine whether Pax2 regulates cell adhesion to maintain cap mesenchyme cells. In Aim 3, we will compare Pax2 function before and after the onset of nephron differentiation. Our proposed studies should give better insights into the genetic regulatory mechanisms for nephron progenitor cells, which may lead to development of novel therapeutic paradigms for kidney diseases in humans.