Engineering scalable collecting duct networks for functional kidney tissue

为功能性肾组织设计可扩展的集合管网络

• 批准号: 10674480
• 负责人: Kayla Wolf
• 金额: $ 7.43万
• 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 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10674480
• 关键词: 3-Dimensional; Automobile Driving; Biocompatible Materials; Biological Assay; Biological Models; Biomedical Engineering; Biomedical Research; Carrier Proteins; Cell Culture Techniques; Cells; Clinical; Collagen; Communication; Coupled; Data Analyses; Development; Development Plans; Disease model; Distal; Doctor of Philosophy; Drainage procedure; Drug Screening; Duct (organ) structure; Engineering; Environment; Epithelium; Excision; Experimental Designs; Extracellular Matrix; Fellowship; Filtration; First Pregnancy Trimester; Gene Expression; Genes; Goals; Human; Human Engineering; In Vitro; Kidney; Knowledge; Mentorship; Mesenchyme; Metanephric Diverticulum; Methodology; Methods; Modeling; Morphogenesis; Morphology; Nephrons; Organoids; Patients; Pattern; Phenotype; Physiology; Play; Porosity; Protocols documentation; Renal Replacement Therapy; Research; Research Personnel; Role; System; Techniques; Testing; Tissue Engineering; Tissues; Training; Tubular formation; United States National Institutes of Health; Universities; Ureter; Work; biofabrication; bioprinting; career; career development; design; differentiation protocol; fabrication; human embryonic stem cell; human pluripotent stem cell; induced pluripotent stem cell; insight; interstitial; network models; post-doctoral training; programs; protein expression; protein function; research and development; response; responsible research conduct; scaffold; skills; stem cells; tool

PROJECT SUMMARY / ABSTRACT The proposal outlines an integrated research and career development plan for Kayla Wolf, PhD, to complete postdoctoral training under the mentorship of sponsor Jennifer Lewis, ScD, and co-sponsor Lisa Satlin, MD. The overarching goal of the proposed project to develop a functional collecting duct network that is derived from human pluripotent stem cells and interconnected with a single drainage outlet. This network could serve as a model system for hypothesis testing, disease modeling, and drug screening or could interconnect directly with nephron-rich organoids to facilitate filtrate drainage in 3D kidney tissues. Recognizing that the extracellular matrix (ECM) plays a crucial role in development, this proposal with both investigate the role of ECM in collecting duct differentiation and leverage biomaterials as a powerful tool for guiding tissue form and function. Development of the collecting duct system will be accomplished by the completion of three aims. First, ureteric bud cells (UB, collecting duct precursors) generated from emerging differentiation protocols will be validated, and the effects of adapting the protocol to scalable culture methods on UB phenotype will be tested. Second, the role of extracellular matrix (ECM) composition on UB morphological and functional differentiation will be determined. Finally, the effects of fabricating a drainage outlet in a branching UB network on transport protein expression and function will be determined. Successful completion of this proposal will elucidate the role of ECM in driving collecting duct development, advance biofabrication methodology, and produce critically needed engineering solutions for generating functional kidney tissue. Dr. Wolf (PI) was supported by an NIH F31 fellowship (F31 CA228317-01) during her graduate research, where she established expertise in biomaterials, bioengineering, and mechanobiology. Under NIH F32 support, the PI receive extensive training in biofabrication and renal physiology at Harvard University, which cultivates a well- established, globally-leading biomedical research environment. The career development plan is designed to equip the PI with the necessary knowledge and skills for a successful career as an independent academic researcher.

项目概要/摘要 该提案概述了凯拉·沃尔夫博士的综合研究和职业发展计划，以完成 在赞助商 Jennifer Lewis（科学博士）和共同赞助商 Lisa Satlin（医学博士）的指导下进行博士后培训。这 拟议项目的总体目标是开发一个功能性集合管网络，该网络源自 人类多能干细胞并与单个排水口互连。该网络可以作为 用于假设检验、疾病建模和药物筛选的模型系统，或者可以直接与 富含肾单位的类器官，促进 3D 肾组织中的滤液引流。认识到细胞外基质 (ECM) 在发育中起着至关重要的作用，该提案同时研究了 ECM 在集合管中的作用 分化并利用生物材料作为指导组织形态和功能的强大工具。发展 集合管系统将通过完成三个目标而实现。首先，输尿管芽细胞（UB， 由新兴分化方案产生的集合管前体）将得到验证，并且效果 将测试使该协议适应 UB 表型的可扩展培养方法。二、作用 细胞外基质（ECM）组成对UB形态和功能分化的影响将被确定。 最后，在分支 UB 网络中制作排水口对转运蛋白表达的影响 和功能将被确定。该提案的成功完成将阐明 ECM 在驱动中的作用 集管开发，先进的生物制造方法，并生产急需的工程 用于产生功能性肾组织的解决方案。 Wolf 博士（PI）在研究生研究期间获得了 NIH F31 奖学金 (F31 CA228317-01) 的支持，其中 她在生物材料、生物工程和机械生物学方面建立了专业知识。在 NIH F32 的支持下，PI 在哈佛大学接受生物制造和肾脏生理学方面的广泛培训，培养了良好的 建立了全球领先的生物医学研究环境。职业发展计划旨在 为 PI 提供作为独立学者取得成功职业生涯所需的知识和技能 研究员。