Mechanisms of tubule interconnection

肾小管互连机制

基本信息

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
项目类别：
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

项目摘要

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.

描述（由适用提供）：肾脏疾病在美国影响超过2000万人，是第八大死亡原因。它也是慢性病（例如高血压和糖尿病）最昂贵的并发症之一。肾脏再生的进步可能会减慢或反向肾衰竭，将对人类健康产生重大影响。基于细胞的肾脏再生疗法的长期目标是使用工程的肾脏祖细胞来产生新的肾单位并替代受伤的肾脏中受损的肾脏受损。还正在探索肾脏祖细胞，用于在工程或天然器官支架中生成肾单位。无论哪种情况，肾单位功能都需要专利管腔，以进行滤波，处理和稳态；即适当的管道。小管腔的互连是在肾脏发育过程中正常通过不同S形体细胞侵袭输尿管上皮的。但是，在成熟的肾脏中，植入的肾脏祖细胞可能会分化为管，但无法连接到现有的分支收集系统，并且不促进肾功能。该建议旨在通过鉴定介导肾管接收导管融合的生长因子来克服这一障碍，并确定如何在肾脏再生过程中诱导小管互连。 Using the zebrafish adult kidney as a model of synchronous nephron tube-collecting duct fusion we will 1) screen well-established Wnt and FGF signaling pathways with small molecule inhibitors and assay tube interconnection and 2) test the effect of spatially and temporarily restricted expression of growth factors or dominant negative small GTPase signaling inhibitors on nephron tube-collecting duct fusion.这些研究将提供有关基于细胞和基于组织的肾脏再生疗法所需的必不可少但知识的细胞机制的重要新见解。