RECODE: Rules-based Morphogenesis of Brain Organoids through Synthetic Gene Circuits

据估计，美国每年因大脑疾病而损失8000亿美元。一般来说，人脑不能直接进行实验。然而，患者来源的干细胞可用于创建类器官，其部分类似于原始组织。脑源性类器官已被证明有助于理解大脑发育和疾病，但目前还不能完全复制人脑的复杂性和连通性。在这个项目中，大脑类器官将被设计成更可靠地发展成一个类似大脑的互连网络。该项目将研究与教育紧密结合。它为大纳什维尔公立学校的科学推广计划提供直接支持，并招募高中生参加研究项目。这些努力将有助于培养下一代科学家和STEM职业工作者。脑类器官的产生利用了人类多能干细胞（hPSC）整合全局和局部形态发生线索以进行自组装和分化的能力。构建脑类器官需要添加激活或抑制特定信号通路的外部线索。hPSC通过建立形态发生剂激动剂和拮抗剂的内部梯度的网络来解释这种信号传导混合物。信号中心协调胚胎发育。如果没有它们，类器官的产生会导致大小，形状和细胞组织的不一致。这些特征必须在脑类器官中忠实地复制。该项目的目标是建立产生大脑皮质类器官所需的分子逻辑和设计规则。我们的目标是创建一个独立的系统，具有可重复的和定义的架构，大小和细胞组成。重新连接细胞网络将引导细胞自主地对它们的微环境做出反应。这些细胞将可重复地模板化早期皮质生成，同时在后期阶段平衡祖细胞增殖和分化。所揭示的原理将指导脑类器官的利用，以了解发育和疾病，并筛选潜在的治疗方法。了解大脑中控制高阶结构形成的设计规则可能适用于其他类型的组织。该项目由ENG/CBET的工程生物学和健康集群以及BIO/MCB的系统和合成生物学集群共同支持。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Brain disorders cost the US an estimated $800 billion each year. In general, the human brain cannot be experimented on directly. However, patient-sourced stem cells can be used to create organoids, which partially resemble the tissue of origin. Brain-derived organoids have proven to be helpful in understanding brain development and disease, but currently do not fully replicate the complexity and connectivity of the human brain. In this project, brain organoids will be engineered to more reliably develop into an interconnected network resembling the brain. The project tightly integrates research with education. It provides direct support for scientific outreach programs to Metro Nashville Public Schools and recruitment of high school students to participate in the research project. These efforts will help develop the next generation of scientists and STEM-career workers.Brain organoid generation exploits the ability of human pluripotent stem cells (hPSCs) to integrate global and local morphogenetic cues to self-assemble and differentiate. Building brain organoids requires addition of external cues that activate or suppress specific signaling pathways. The hPSCs interpret this signaling cocktail through networks that establish internal gradients of morphogen agonists and antagonists. Signaling centers coordinate embryo development. Without them, organoid production can lead to inconsistencies in size, shape, and cellular organization. These features must be faithfully replicated in brain organoids. The goal of this project is to establish the molecular logic and design rules required to generate cerebral cortical organoids. The objective is to create a self-contained system with reproducible and defined architecture, size, and cellular composition. Rewiring cellular networks will direct cells to autonomously respond to their microenvironment. These cells will reproducibly template early corticogenesis while balancing progenitor cell proliferation and differentiation during later stages. The principles uncovered will guide the utilization of brain organoids for understanding development and disease, and for screening potential therapeutics. Understanding the design rules that govern higher-order structure formation in the brain may potentially be applied to other types of tissues. This further opens the possibility of engineering tissue replacements for transplantation.This project is being jointly supported by the Engineering Biology and Health Cluster in ENG/CBET and the Systems and Synthetic Biology Cluster in BIO/MCB.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.