Mechanisms of tubule interconnection

肾小管互连机制

• 批准号: 8995457
• 负责人: IAIN A. DRUMMOND
• 金额: $ 36.56万
• 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: 2015-09-23 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8995457
• 关键词: Adult; Affect; Area; Biological Assay; Blood; Cause of Death; Cell Therapy; Cell physiology; Cells; Chronic Disease; Development; Diabetes Mellitus; Distal; Dominant-Negative Mutation; Duct (organ) structure; Embryo; Engineering; Environment; Epithelial; Epithelial Cells; Epithelium; Event; Excretory function; Fibroblast Growth Factor; Gentamicins; Goals; Growth Factor; Health; Homeostasis; Human; Hypertension; Implant; Injury; Invaded; Investments; Kidney; Kidney Diseases; Kidney Failure; Legal patent; Liquid substance; Mediating; Modeling; Monomeric GTP-Binding Proteins; Natural regeneration; Nephrons; Organ; Pathway interactions; Plumbing; Population; Process; Renal Replacement Therapy; Renal function; Renal tubule structure; Shapes; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Signaling Molecule; Stem cells; System; Tamoxifen; Testing; Time; Tissues; Transgenic Organisms; United States; Ureter; Work; Zebrafish; base; cell type; embryonic stem cell; in vivo; induced pluripotent stem cell; inhibitor/antagonist; injured; insight; interest; kidney cell; morphogens; nephrogenesis; neuronal cell body; progenitor; promoter; public health relevance; scaffold; small molecule

 DESCRIPTION (provided by applicant): Kidney disease affects more than 20 million people in the United States and is the 8th leading cause of death. It is also one of the costliest complications of chronic illness, such as hypertension and diabetes. Advances in kidney regeneration that could slow or reverse progression to kidney failure will have a major impact on human health. A long-term goal of cell-based therapies for kidney regeneration is to use engineered renal progenitor cells to generate new nephrons and replace damaged nephrons in injured kidneys. Renal progenitor cells are also being explored for use in generating nephrons ex vivo in engineered or natural organ scaffolds. In either case, nephron function requires a patent lumen for filtrate flow, processing, and homeostasis; i.e., proper plumbing. Tubule lumen interconnections are established normally during renal development by invasion of the ureter epithelium by cells of the distal S-shaped body. However, in a mature kidney, implanted renal progenitor cells may differentiate into tubules but fail to connect to an existing branched collecting system and do not contribute to kidney function. This proposal aims to overcome this hurdle by identifying growth factors that mediate nephron tubule-collecting duct fusion and determine how tubule interconnection can be induced during renal regeneration. Using the zebrafish adult kidney as a model of synchronous nephron tubule-collecting duct fusion we will 1) screen well-established Wnt and FGF signaling pathways with small molecule inhibitors and assay tubule interconnection and 2) test the effect of spatially and temporally restricted expression of growth factors or dominant negative small GTPase signaling inhibitors on nephron tubule- collecting duct fusion. These studies will provide important new insights about an essential but understudied cellular mechanism that is required for cell and tissue-based renal regeneration therapies.