The progressive loss of nephrons and deterioration of renal function is a hallmark or several chronic human diseases. The generation of new nephrons in adult kidneys, a goal of many stem cell based inquiries, is best studied in the context of regenerative nephrogenesis in adult animals. This proposal aims to study the role of FGF signaling in the novel context of injury-induced nephrogenesis in the adult zebrafish mesonephros.
The specific aims of the proposal will answer the questions: 1. What is the role of FGF signaling in activation and aggregation of adult nephron progenitor cells? 2. What are the FGF ligands and receptors required for kidney regeneration? 3. Genetic analysis of FGF signaling pathways in development and regeneration. FGF signaling is integral to the morphogenesis and identity dynamics of cells in development and disease. FGF signaling is an established regulator of renal tubule growth and is implicated in chronic kidney disease. While mammals lack the ability to produce new nephrons after initial organogenesis, the zebrafish mesonephros continues to produce new nephrons throughout the lifespan. Further, the adult zebrafish pronephros responds to acute kidney injury by rapid and reproducible mass neo- nephrogenesis. This proposed work will utilize this model system to identify important signaling related to the process of adult stem cell activation in renal injury, will provide important information relevant to the utilization of stem cells as therapeutics, and will result in genetic tols for addressing questions related to adult stem cells in the kidney.
FGF signaling is involved in many aspects of tissue development and maintenance, including development, cancer and stem cell fate specification, and tissue regeneration. Understanding the dynamics of FGF signaling during the process of nephron precursor activation events in the regenerating fish kidney can provide mechanistic information relating to correct and aberrant developmental processes and potential for regeneration of tissue in humans.
