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Identifying pathways required for integration of kidney organoid and host epithelia

确定肾类器官和宿主上皮细胞整合所需的途径

基本信息

批准号：
10053465
负责人：
IAIN A. DRUMMOND
金额：
$ 62.78万
依托单位：
MOUNT DESERT ISLAND BIOLOGICAL LAB
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10053465
关键词：
3-Dimensional Adult Basement membrane Bioinformatics Biological Assay Blood Cause of Death Cell Aggregation Cell Culture System Cell Culture Techniques Cell fusion Cells Coupled Data Development Dialysis procedure Distal End stage renal failure Engineering Engraftment Environment Epithelial Epithelial Cells Epithelium Event Excision Extracellular Matrix Fibroblast Growth Factor Filtration Fishes Genetic Goals Human Immune Implant In Situ Hybridization In Vitro Injury Invaded Investigation Kidney Kidney Diseases Kidney Failure Kidney Transplantation Legal patent Ligands Liquid substance Mammalian Cell Matrix Metalloproteinases Mediating Methodology Modeling Molecular Mus Mutation Natural regeneration Nephrons Organoids Output Pathway interactions Patients Pattern Phenotype Play Plumbing Pluripotent Stem Cells Process Renal function Renal tubule structure Reporting Role Series Signal Pathway Signal Transduction Site Structure System TIMP1 gene Technology Testing Tissue Inhibitor of Metalloproteinases Tissues Urine WNT Signaling Pathway WNT9A gene Work Zebrafish base experimental study genetic analysis glucose uptake in vivo insight mutant nephrogenesis polarized cell prevent programs receptor recruit regenerative therapy renal damage repaired scale up specific biomarkers stem cells three dimensional cell culture tool transcriptomics urinary

项目摘要

Project Summary Kidney disease is the 9th leading cause of death in the U.S. Because few therapies exist to prevent or slow progression, over 700,000 patients have End Stage Renal Disease. These patients are treated with dialysis or renal transplant, the latter resulting in markedly superior survival. However, kidney donors are limited and there is an important unmet need for strategies that enhance renal repair or generate new nephrons for renal replacement. Pluripotent stem cell derived organoids display key features of differentiated kidney tubules and glomerular structures in vitro, and we have shown that they generate patterned nephrons in vivo displaying kidney functions such as filtration and glucose uptake by the proximal tubule. To develop this technology for renal replacement, stem cell derived tubules must be connected to host tubules for urinary output. Our recent work in the zebrafish demonstrated that FGF signaling acts as a chemotactic signal to recruit and polarize cells at sites of new nephron formation and canonical Wnt signaling is required for invasive cell rearrangement to connect tubule lumens. Additional signaling pathways including non-canonical wnt signaling are also likely to play a role in tubule interconnection. To fully explore the requirements for tubule interconnection we have established a synergistic, three-part discovery platform comprising 1) genetic analysis of in vivo new nephron addition in the regenerating zebrafish adult kidney, 2) in vitro 3D cell culture analysis of mammalian epithelial fusion, and 3) in vivo stem cell-derived kidney organoid engraftment to a host mouse collecting system. We will combine these approaches to analyze multiple steps of the tubule fusion process involving 1) recruitment of nephron progenitor cells to target epithelia, 2) removal of intervening ECM/basement membranes, 3) patterned collective cell invasion of target epithelia, and 4) establishment of a continuous patent new lumen to convey the nephron filtrate. These studies will provide important new insights about an essential but understudied cellular mechanism that will be required for in vivo engraftment of new kidney tissue-based renal regeneration therapies.

项目总结