Genetic Regulation of Nephron Progenitor Cells in the Mammalian Kidney

哺乳动物肾脏中肾单位祖细胞的遗传调控

• 批准号: 8847550
• 负责人: Akio Kobayashi
• 金额: $ 24.79万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8847550
• 关键词: Genetic; Regulation; Nephron; Progenitor; Cells

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.

描述(申请人提供)：肾脏的基本功能单位，肾单位，是在肾脏器官发生过程中重复产生的。肾病时，肾单位丢失，纤维化间质扩大。虽然哺乳动物的肾脏可以再生部分受损的肾单位，但没有观察到新的肾单位的形成。在肾脏发育过程中，我们以前发现帽间充质细胞是一种多能自我更新的肾单位祖细胞。我们的初步数据表明，肾单位和间质形成不同的间隔，具有明显的谱系边界。目前尚不清楚肾单位和间质组织是如何确定和维持的。我们的初步数据表明，转录因子PAX2在肾器官发生过程中通过抑制向间质的反式分化来维持肾单位祖细胞。因此，Pax2活性在肾脏器官发生过程中建立了肾单位和间质谱系之间的发育边界。然而，Pax2如何维持肾单位祖细胞的活性尚不清楚。此外，尽管我们的数据表明Pax2是维持肾单位祖细胞所必需的，但尚不清楚Pax2活性是否足以确定肾单位祖细胞的状态。在这项研究中，我们建议进一步研究Pax2基因在肾单位发育中的作用。在目标1中，我们将对肾单位前体细胞的Pax2功能进行详细的分子分析。在目标2中，我们将研究Pax2是否调节细胞黏附以维持帽间充质细胞。在目标3中，我们将比较Pax2在肾单位分化开始前后的功能。我们提出的研究应该能更好地了解肾单位祖细胞的基因调控机制，这可能会导致人类肾脏疾病的新治疗范例的开发。