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Investigating mechanical regulation of nephrogenesis using viscoelastic biomaterials and kidney organoids

使用粘弹性生物材料和肾类器官研究肾发生的机械调节

基本信息

批准号：
10536817
负责人：
Bryan Nerger
金额：
$ 6.72万
依托单位：
HARVARD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10536817
关键词：
3-Dimensional Address Adult Affect Alginates Architecture Biocompatible Materials Biology Biomechanics Biomedical Engineering Cell Proliferation Cells Chronic Kidney Failure Collaborations Complex Computer Analysis Computer Models Cues Dependence Developmental Biology Dialysis procedure Disease Progression Drug Screening Embryo Engineering Extracellular Matrix Gene Expression Profile Goals Growth Hospitals Human Hydrogels In Vitro Kidney Kidney Diseases Kidney Transplantation Knowledge Mechanics Mediator of activation protein Mesenchymal Mesenchyme Modeling Molecular Morbidity - disease rate Morphology Mus Natural regeneration Nephrons Organoids Patients Public Health Regulation Renal dialysis Research Research Personnel Role Structure Techniques Testing Time Tissues Training Universities Woman Work alternative treatment base cell behavior design experimental analysis human pluripotent stem cell in vivo insight interstitial mechanical behavior mechanical properties mechanical signal migration mortality nephrogenesis nephron progenitor repair strategy repaired response skills stem cell differentiation stem cells three dimensional cell culture transplantation therapy viscoelasticity

项目摘要

PROJECT SUMMARY Chronic kidney disease (CKD) affects ~15% of adults in the US and is associated with the irreversible loss of nephrons, which form the basic functional unit of the kidney. There is currently no cure for CKD, and treatments such as kidney transplantation and dialysis have a high morbidity and mortality. Developing strategies for repairing or replacing nephrons will address this significant public health problem by providing an alternative treatment for patients and a new model of kidney development and disease for drug screening. Mechanical properties of the extracellular matrix, such as stiffness and viscoelasticity, regulate key aspects of cell behavior that drive nephrogenesis in vivo, including proliferation, differentiation, and migration. However, while the molecular mediators that drive nephrogenesis have been studied extensively, the role of matrix mechanics in nephrogenesis remains unclear. Beyond elucidating the role of biomechanics in kidney development, understanding the functional role of the mechanical microenvironment in nephrogenesis will help to inform engineering strategies to reproduce nephrogenesis in vitro. The goal of this proposal is to integrate 3D viscoelastic alginate hydrogels and kidney organoids to test the hypothesis that the mechanical microenvironment regulates nephrogenesis. The first aim is to determine the role of matrix stiffness and viscoelasticity in the differentiation of human pluripotent stem cells into multipotent nephron progenitor cells and the subsequent cellular organization of nephrons in kidney organoids. The second aim is to investigate how hydrogel architecture affects the morphology and maturation of kidney organoids. These aims will be accomplished by integrating bioengineering, biomaterials, developmental biology, computational modeling, and mechanical characterization techniques. Completion of this project will deepen our understanding of the role of the mechanical microenvironment in the formation of nephrons and will fill a substantial knowledge gap regarding our fundamental understanding of kidney development and stem cell differentiation in vivo. This work will also illuminate design principles for engineering new biomaterials that support nephrogenesis in culture and the regeneration of nephrons in vivo. The training will take place in the Mooney Lab at Harvard University in collaboration with the Mahadevan Lab at Harvard University and the Bonventre Lab at Brigham and Women's Hospital. The training plan will enhance the applicant’s skills in biomaterials design, quantitative biology, and kidney organoid culture and provide a broad understanding of kidney development and disease.

项目总结