FGF Signaling in Zebrafish Mesonephric Kidney Regeneration

斑马鱼中肾再生中的 FGF 信号传导

• 批准号: 9147469
• 负责人: Thomas Fermin Gallegos
• 金额: $ 6.53万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9147469
• 关键词: Activities of Daily Living; Acute Renal Failure with Renal Papillary Necrosis; Address; Adult; Affect; Alleles; Biological Assay; Biological Models; CRISPR/Cas technology; Cell Lineage; Cell Proliferation; Cell Therapy; Cells; Chronic; Chronic Kidney Failure; DUSP6 protein; Deterioration; Development; Developmental Process; Disease; Dominant-Negative Mutation; Epithelium; Event; Exons; FGF20 gene; FGF8 gene; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Fishes; Foundations; Gene Expression; Gene Targeting; Generations; Genes; Genetic; Goals; Growth; Health; Human; In Situ; In Situ Hybridization; Injury; Injury to Kidney; Kidney; Knock-out; Knowledge; Ligands; Longevity; Maintenance; Malignant Neoplasms; Mammals; Mediating; Mesonephric structure; Metronidazole; Modeling; Morphogenesis; Natural regeneration; Nephrons; Nitroreductases; Organ; Organogenesis; Outcome; Patients; Pharmacology; Population; Process; Proliferating; Pronephric structure; Receptor Gene; Regenerative response; Renal function; Renal tubule structure; Reporter; Reproducibility; Reverse Transcriptase Polymerase Chain Reaction; Role; Scheme; Signal Pathway; Signal Transduction; Site; Specificity; Staining method; Stains; Stem cells; Testing; Therapeutic; Time; Tissues; Transgenes; Transgenic Model; Transgenic Organisms; United States; Vesicle; WNT Signaling Pathway; Work; Zebrafish; adult stem cell; base; cell type; conditional mutant; follow-up; genetic analysis; homologous recombination; human disease; human embryonic stem cell; in vivo; induced pluripotent stem cell; inhibitor/antagonist; injured; kidney cell; mature animal; mutant; nephrogenesis; novel; progenitor; public health relevance; receptor; regenerative; regenerative therapy; response; response to injury; stem cell differentiation; stem cell fate specification; success; tissue regeneration

 DESCRIPTION (provided by applicant): 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.

 描述（由申请人提供）：肾单位的逐渐丧失和肾功能的恶化是几种慢性人类疾病的标志。成人肾脏中新肾单位的生成是许多基于干细胞的研究的目标，最好在这种情况下进行研究。该提案旨在研究 FGF 信号在成年斑马鱼中肾损伤诱导的肾发生的新背景中的作用。该提案的具体目标将回答以下问题： 1. FGF 信号传导在成体肾单位祖细胞的激活和聚集中发挥什么作用？ 2. 肾脏再生所需的 FGF 配体和受体是什么？ 3. FGF 信号传导的遗传分析？ FGF 信号传导是发育和疾病中细胞形态发生和身份动态的组成部分。FGF 信号传导是肾小管生长的既定调节因子，与慢性肾脏疾病有关。哺乳动物在最初的器官发生后缺乏产生新肾单位的能力，斑马鱼的中肾单位在整个生命周期中持续产生新的肾单位。此外，成年斑马鱼的前肾单位通过快速且可重复的大规模肾单位发生来应对急性肾损伤。模型系统可识别与肾损伤中成体干细胞激活过程相关的重要信号传导，将提供与利用干细胞作为治疗药物相关的重要信息，并将产生解决与肾脏成体干细胞相关问题的遗传工具。