CAREER: Synthetic ‘remote control’ of kidney tissue formation towards large-scale models of congenital disease

职业：通过合成“远程控制”肾组织的形成来构建大规模先天性疾病模型

• 批准号: 2047271
• 负责人: Alex Hughes
• 金额: $ 52.99万
• 依托单位: University of Pennsylvania
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2047271&HistoricalAwards=false
• 关键词: CAREER; Synthetic; remote; control; kidney

The goal of this Faculty Early Career Development (CAREER) project is to create kidney tissues in an environment mimicking that of natural development in the body. The kidney is a hotspot for birth defects that affect the size, number, and arrangement of filtration units, called nephrons, and the tubules that carry urine within the kidney and out to the bladder. This project seeks determine the engineering rules that guide tubules as they form in the kidney and then to mimic nephron fusion with the tubule network. Together, these activities will create more "true-to-life" kidney tissues in a dish that can be used to study the origin of kidney birth defects at a fundamental level and inform new intervention strategies for childhood and adult diseases that originate from such defects. Two integrated educational projects are designed to equip a new generation of young scientists with the quantitative skills needed to contribute to the emerging discipline of “developmental engineering." The first project is creating a summer research experience for undergraduate students in which participation will be broadened by focusing recruitment efforts on under-represented minority, women, and first-generation students through several partnerships based on the investigator’s commitment to removing barriers to the use and generation of technology by all people. The second project is creating free and publicly available lesson/lecture plan modules through a crowd science platform called quanti.us. These modules will serve high school and undergraduate sciences educators and aim to stoke student interest in cutting-edge scientific problems while equipping them with quantitative problem-solving approaches.The investigator’s long-term research goal is to develop advanced biomanufacturing strategies based on the control of tissue morphogenesis with expectations that efforts will lead to the creation of human tissues with sufficient complexity to be models for drug development or directly in regenerative medicine. Toward this goal, this CAREER project is focused on mimicking nephron differentiation and fusion with the ureteric tree in synthetic tissue models of the developing kidney, which will be accomplished by generating human kidney tubule networks with controlled size and connectivity and then directing nephron formation at many spatial sites within them to better capture kidney structure at cm-scale. The project addresses the need for models of kidney development outside of the body with sufficient organization across length-scales to properly study common development diseases of the kidney such as CAKUT (congenital anomalies of the kidney and urinary tract), which is marked by incomplete organization of epithelial networks necessary for kidney function. Studies are designed to test the hypothesis that the mechanical microenvironment of kidney epithelial bud branching into the surrounding extracellular matrix (ECM) "mesenchyme" during development sculpts tubule elongation and geometric spacing. The research plan is organized under two specific aims: (1) Determine the mechanical contribution of the tissue micro-environment to epithelial tubule guidance using tissue-engineered mimics of the mesenchyme and an existing FEM model and (2) Engineer nephron integration into dynamic tissue scaffolds through spatially guided differentiation, leveraging cell patterning, biochemical, and optogenetic approaches to direct the differentiation of early nephron lineages at many specific sites in tubule networks within dynamic scaffolds at once. The ability to mimic human kidney development beyond the level of a single nephron or tubule will finally create opportunities to study and develop therapies for congenital kidney diseases.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

这个教师早期职业发展（职业）项目的目标是在模仿体内自然发育的环境中创建肾脏组织。肾脏是一种用于影响过滤单元的大小，数量和排列的先天缺陷的热点，称为肾单位，以及在肾脏内携带尿液并送到膀胱的块茎。该项目寻求确定指导管在肾脏形成时引导管道的工程规则，然后模仿Tubele网络。这些活动一起将在菜肴中创建更多的“真实”肾脏组织，该菜肴可用于研究基本水平的肾脏出生缺陷的起源，并为儿童和成人疾病的新干预策略提供源于此类缺陷的新干预策略。两个综合的教育项目旨在为新一代的年轻科学家配备有助于“发展工程”的新兴学科所需的定量技能。第一个项目是为本科生创造夏季研究经验，在该研究中，通过将招聘工作集中在代表性不足的少数群体，妇女和第一代学生上，通过研究人员承诺取消所有人对技术使用和生成技术的障碍，可以扩大参与。第二个项目是通过称为Quanti.us的人群科学平台创建免费的公开课程/讲座计划模块。这些模块将为高中和本科科学教育者提供服务，并旨在使学生对最先进的科学问题的兴趣，同时为他们提供定量的解决问题解决方法。研究者的长期研究目标是基于对组织形态的控制进行先进的生物制造策略，并期望将人类组织的努力与富裕的人进行固定或直接的药物开发。为了实现这一目标，该职业项目的重点是模仿发育中肾脏的合成组织模型中的肾单位分化和融合与输尿管树的融合，这将通过产生人类的肾脏小管网络来实现，然后在其内部的许多空间位点引导肾小管形成的人类肾脏小管网络，以更好地捕获CM-Scale的肾脏结构。项目解决了对体内肾脏发育模型的需求，该模型在跨长度尺度上足够的组织来适当研究肾脏的常见发育疾病，例如Cakut（肾脏和尿路的先天异常），这是由不完全的肾脏功能上皮网络组织的不完全组织所标记的。研究旨在检验以下假设：在发育雕塑过程中，肾上皮芽的机械微环境将肾上皮芽分支进入周围的细胞外基质（ECM）“间质”管道伸长和几何间距。研究计划是在两个具体目的下组织的：（1）确定组织微观环境对上皮管指导的机械贡献，使用组织工程化的模拟物和现有的FEM模型和现有的FEM模型，以及（2）工程师Nephron通过空间分化，通过空间差异化，将nephron整合到动态的分化，杠杆化，并将其置于空间上的分化中，Birove and loperation，Birovering，Birovering，Birovering，Birove，Birovering，Birove，Birove，Birove，Birove scaffords offerication，Birove scaffords coffriending scaffers，肾单位谱系在动态支架内的许多特定位点上都在许多特定位点上。模仿人类肾脏发育的能力超出了单个肾单位或管的水平，最终将创造机会来研究和开发先天性肾脏疾病的疗法。该奖项反映了NSF的法定任务，并被认为是通过基金会的知识分子和更广泛影响的评估标准来通过评估来评估的。