Osr1 and Wnt signaling in nephrogenesis and kidney regeneration

描述(申请人提供)：先天性肾脏异常是儿童肾脏疾病的主要原因，包括肾发育不全、幼年性囊性疾病、肾病综合征和肾母细胞瘤。了解肾脏发育不仅指导我们对先天性肾脏疾病的理解，还为开发恢复肾功能的干预措施提供了一个框架。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；在这项提议中，我们旨在了解调节和信号分子如何发挥作用来驱动肾脏的初始形成，以及如何利用它们来促进肾小管的再生。我们已经发现，奇数跳过相关1(Osr1)基因是调节斑马鱼所有类型的肾单位细胞的发育和小鼠肾脏发生所必需的。我们建议扩大我们对斑马鱼和小鼠的osr1功能的比较分析，以表征osr1在足细胞分化中的独特细胞自主作用以及osr1在管状细胞和血管母细胞分化中的非细胞自主作用。斑马鱼胚胎中osr1缺陷细胞的镶嵌分析，小鼠肾脏外植体培养中的敲除方法，以及条件Osr1基因敲除小鼠的产生，将有助于我们进一步了解osr1在肾脏细胞分化和肾单位模式形成中的保守功能。在斑马鱼中，osr1缺失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信号和卷曲受体在以前未知的环境中的功能，包括肾管形成、肾单位模式形成和肾损伤后的恢复。从这项工作中获得的见解将指导未来的努力，指导肾脏前体细胞分化，并在损伤后恢复肾小管功能。

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.