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

• 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
• 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

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.

项目摘要 慢性肾脏疾病（CKD）影响了美国约15％的成年人，并且与不可逆转的丧失有关 肾单位，构成肾脏的基本功能单元。目前无法治愈CKD和治疗 例如肾脏移植和透析具有很高的发病率和死亡率。制定策略 维修或替换肾单位将通过提供替代方案来解决这个重大的公共卫生问题 患者的治疗以及用于药物筛查的肾脏发育和疾病的新模型。 细胞外基质的机械性能，例如刚度和粘弹性，调节了关键方面 驱动体内肾病的细胞行为，包括增殖，分化和迁移。然而， 虽然驱动肾脏发生的分子介质已经进行了广泛研究，但矩阵的作用 肾病中的力学尚不清楚。除了阐明生物力学在肾脏中的作用 开发，了解机械微环境在肾脏发生中的功能作用将有助于 告知工程策略以在体外再现肾病。该提议的目的是整合 3D粘弹性算法水凝胶和肾脏器官，以检验机械的假设 微环境调节肾病。第一个目的是确定矩阵刚度和 人多能干细胞分化为多能肾单位祖细胞和 随后的肾脏器官肾单位细胞组织。第二个目的是调查如何 水凝胶结构会影响肾脏器官的形态和成熟。这些目标将是 通过整合生物工程，生物材料，发育生物学，计算建模和 机械表征技术。 该项目的完成将加深我们对机械微环境在 形成肾单位，并将填补有关我们对我们对的基本理解的巨大知识差距 体内肾脏发育和干细胞分化。这项工作还将阐明 工程新的生物材料，支持培养和体内肾肾脏再生的肾病。 该培训将在哈佛大学的穆尼实验室与Mahadevan实验室合作 哈佛大学和杨百翰和妇女医院的Bonventre实验室。培训计划将增强 申请人在生物材料设计，定量生物学和肾脏器官文化方面的技能，并提供广泛的 了解肾脏发育和疾病。