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Osr1 and Wnt signaling in nephrogenesis and kidney regeneration

Osr1 和 Wnt 信号在肾发生和肾再生中的作用

基本信息

批准号：
8481540
负责人：
IAIN A. DRUMMOND
金额：
$ 36.94万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-07-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8481540
关键词：
Acute Adolescent Adult Affect Angioblast Animal Model Antibodies Biological Assay Cell Differentiation process Cell Lineage Cell Proliferation Cell Therapy Cells Childhood Chronic Kidney Failure Congenital Abnormality Defect Development Disease Dominant-Negative Mutation Duct (organ) structure Embryo Endothelial Cells Engineering Epithelial Epithelial Cells Fetal Kidney Future Gene Expression Regulation Gene Mutation Gene Transfer Techniques Generations Genes Heat-Shock Response In Situ Injury Intervention Kidney Kidney Diseases Kidney Transplantation Label Larva Learning Length Life Link Maps Mesenchyme Mesoderm Modeling Morphogenesis Mus Mutant Strains Mice Natural regeneration Nephroblastoma Nephrons Nephrotic Syndrome Optics Organ Organism Organogenesis Pattern Pronephric structure Proteins Recovery Renal dialysis Renal function Renal tubule structure Role Signal Transduction Signaling Molecule Staging Stem cells System Transcription factor genes Transgenes Transplantation Urogenital Diseases Work Zebrafish Zinc Fingers assay development cell transformation cell type cellular imaging comparative embryonic stem cell gene function genetic manipulation in vivo insight kidney cell loss of function mutant nephrogenesis novel novel strategies nuclease podocyte protocol development receptor research study transcription factor

项目摘要

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.

描述（由申请人提供）：先天性肾脏异常是儿童肾脏疾病的主要原因，其中包括肾发育不全、青少年囊性病变、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来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。我们发现，奇数跳跃相关 1 (osr1) 基因是调节斑马鱼所有肾单位细胞类型的发育以及小鼠肾发生所必需的。我们建议扩展对斑马鱼和小鼠中 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 在肾小管细胞和成血管细胞分化中的非细胞自主作用。对斑马鱼胚胎中 osr1 缺陷细胞的镶嵌分析、小鼠肾外植体培养中的敲低方法以及条件性 Osr1 敲除小鼠的生成将用于进一步了解 osr1 在肾细胞分化和肾单位模式中的保守功能。斑马鱼中 osr1 缺陷的细胞非自主效应似乎是由于 wnt 信号传导的改变所致。我们将在先前未探索的环境中检查 wnt 信号传导和卷曲受体的功能，包括肾管形成、肾单位模式和肾损伤恢复。从这项工作中获得的见解将指导未来指导肾祖细胞分化和恢复损伤后肾小管功能的努力。