Osr1 and Wnt signaling in nephrogenesis and kidney regeneration

描述（由申请方提供）：先天性肾脏异常是儿科肾脏疾病的主要原因，包括肾发育不全、青少年囊性疾病、肾病综合征和肾母细胞瘤。了解肾脏发育不仅可以指导我们对先天性肾脏疾病的理解，还可以为制定恢复肾功能的干预措施提供框架。许多已知的疾病基因是调节肾脏器官发生的转录因子和信号分子;在本提案中，我们的目标是了解调节和信号分子如何发挥作用以驱动肾脏的初始形成，以及如何利用它们来促进肾小管再生。我们已经发现，odd-skipped related 1（osr 1）基因是调节斑马鱼所有肾单位细胞类型发育和小鼠肾发生所必需的。我们建议扩展我们的比较分析osr 1在斑马鱼和小鼠的功能，以表征一个独特的细胞自主作用osr 1在足细胞分化和非细胞自主作用osr 1在小管细胞和成血管细胞分化。镶嵌分析osr 1缺陷细胞在斑马鱼胚胎中，敲除的方法在小鼠肾脏外植体培养，并产生一个条件Osr 1敲除小鼠将用于进一步了解保守的功能osr 1在肾细胞分化和肾单位图案。斑马鱼osr 1缺陷的细胞非自主效应似乎是由于wnt信号的改变。我们将研究wnt信号和frizzled受体在以前未探索的背景下的功能，包括肾小管形成，肾单位模式，从肾损伤中恢复。从这项工作中获得的见解将指导未来的努力，以指导肾祖细胞分化和恢复损伤后的肾小管功能。

DESCRIPTION (provided by applicant): Congenital abnormalities of the kidney are the major cause of pediatric kidney disease which encompass renal agenesis, juvenile cystic disease, nephrotic syndromes, and Wilms tumor. Understanding kidney development not only guides our understanding of congenital kidney disease but also provides a framework for developing interventions to restore kidney function. Many known disease genes are transcription factors and signaling molecules that regulate kidney organogenesis; in this proposal we aim to understand how regulatory and signaling molecules function to drive initial formation of the kidney and how they might be harnessed to promote kidney tubule regeneration. We have discovered that the odd- skipped related1 (osr1) gene is required to regulate the development of all nephron cell types in zebrafish and for nephrogenesis in mice. We propose extending our comparative analysis of osr1 function in zebrafish and mouse to characterize a distinct cell-autonomous role for osr1 in podocyte differentiation and a non-cell autonomous role for osr1 in tubule cell and angioblast differentiation. Mosaic analysis of osr1-deficient cells in zebrafish embryos, knockdown approaches in mouse kidney explant culture, and generation of a conditional Osr1 knockdout mouse will be used to further our understanding of conserved functions of osr1 in kidney cell differentiation and nephron patterning. Cell non-autonomous effects of osr1-deficiency in zebrafish appear to be due to altered wnt signaling. We will examine wnt signaling and the function of frizzled receptors in previously unexplored contexts including nephric duct formation, nephron patterning, and recovery from kidney injury. Insights gained from this work will guide future efforts to direct kidney progenitor cell differentiation and restore kidney tubule function after injury.