RECODE: New technologies to illuminate and harness cadherins for the reproducible production of cortical tissue in human cerebral organoids

RECODE：阐明和利用钙粘蛋白在人脑类器官中可重复生产皮质组织的新技术

• 批准号: 2034495
• 负责人: Megan McCain
• 金额: $ 150万
• 依托单位: University of Southern California
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-10-15 至 2024-09-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2034495&HistoricalAwards=false
• 关键词: RECODE; New; technologies; illuminate; harness

Brain organoids are clusters of cells that mimic many features of the human brain. As human stem cells differentiate into brain cells, these clusters form. Experimenting on human brains poses many challenges. As a result, brain organoids are used in place of the brain in many studies of early brain development, neurological disorders, and drug discovery research. High variability in the production of brain organoids limits the usefulness in these studies. The goal of this project is to reduce variability through control of cell-cell adhesion during organoid development. The expected outcome will be a collection of cell-cell adhesion interventions that broadly improve the reproducibility of brain organoids production so they can be used as reliable models for human neural development and disease. As part of the project, graduate and undergraduate students will be mentored in team leadership across diverse fields of stem cell biology and engineering.Cell-cell adhesion dynamically remodels the brain during development. Our central hypothesis is that modulation of cell-cell adhesion can manufacture reproducible cerebral organoids from any human stem cell line. New tools to systematically interrogate and modulate cell-cell adhesion at different stages of cerebral organoid differentiation will be developed and implemented. This will be achieved with three specific aims: (1) Develop a suite of technologies to control cell-cell adhesion in human pluripotent stem cells; (2) Identify mechanisms by which cell-cell adhesion regulates neuronal differentiation; and (3) Measure changes in reproducibility upon differentiation with new cell-cell adhesion modulation protocols. The expected outcomes of this project include fundamental knowledge of the role of cell-cell adhesion at early stages of human neuronal differentiation; new technologies to modulate cell-cell adhesion; new technologies to culture and monitor organoids; and a workable differentiation strategy for cerebral organoid development across human pluripotent stem cell lines. These new tools and insights can likely be translated to understand adhesion-based morphogenesis in the differentiation of many cell types beyond cerebral organoids.This project is being jointly supported by the Engineering Biology and Health Cluster in ENG/CBET and the Biomechanics and Mechanobiology Program in ENG/CMMI.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.

脑器官是模仿人脑许多特征的细胞团。当人类干细胞分化为脑细胞时，这些簇就形成了。在人脑上进行实验带来了许多挑战。因此，在许多关于早期大脑发育、神经疾病和药物发现研究中，脑有机化合物被用来代替大脑。脑类器官的高度可变性限制了这些研究的有效性。这个项目的目标是通过控制细胞与细胞之间的黏附来减少有机物发育过程中的可变性。预期的结果将是一系列细胞-细胞黏附干预措施的集合，这些干预措施广泛地提高了脑有机体生产的重复性，因此它们可以用作人类神经发育和疾病的可靠模型。作为该项目的一部分，研究生和本科生将在干细胞生物学和工程的不同领域进行团队领导方面的指导。细胞-细胞黏附在发育过程中动态重塑大脑。我们的中心假设是，细胞-细胞黏附的调节可以从任何人类干细胞系产生可复制的脑器官。将开发和实施新的工具来系统地询问和调节大脑器官分化不同阶段的细胞-细胞黏附。这将通过三个具体目标来实现：(1)开发一套技术来控制人类多能干细胞中的细胞-细胞黏附；(2)确定细胞-细胞黏附调节神经元分化的机制；以及(3)利用新的细胞-细胞黏附调节方案测量分化后重复性的变化。该项目的预期成果包括：关于细胞-细胞黏附在人类神经元分化早期阶段的作用的基础知识；调节细胞-细胞黏附的新技术；培养和监测有机体的新技术；以及在人类多能干细胞系中为脑有机体发育制定可行的分化策略。这些新的工具和见解很可能被转化为在脑器官以外的许多细胞类型的分化中基于黏附的形态发生。该项目由ENG/CBET中的工程生物学和健康集群以及ENG/CMMI中的生物力学和机械生物学计划联合支持。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。