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

据估计，大脑疾病每年给美国造成8000亿美元的损失。一般来说，人脑不能直接用来做实验。然而，患者来源的干细胞可以用来制造类器官，这部分类似于起源的组织。脑源性有机化合物已被证明有助于了解大脑发育和疾病，但目前还不能完全复制人脑的复杂性和连接性。在这个项目中，大脑有机体将被设计成更可靠地发展成类似大脑的相互连接的网络。该项目将研究与教育紧密结合起来。它为纳什维尔大都会公立学校的科学推广计划提供直接支持，并招募高中生参与研究项目。这些努力将有助于培养下一代科学家和STEM职业工作者。大脑器官代利用人类多能干细胞(HPSCs)整合全球和局部形态发生线索的能力，进行自我组装和分化。建立大脑有机体需要额外的外部信号来激活或抑制特定的信号通路。HPSC通过建立形态激动剂和拮抗剂的内部梯度的网络来解释这种信号鸡尾酒。信号中心协调胚胎发育。如果没有它们，有机物质的生产可能会导致大小、形状和细胞组织的不一致。这些特征必须在大脑器官中忠实地复制。这个项目的目标是建立产生大脑皮层有机体所需的分子逻辑和设计规则。我们的目标是创建一个自给自足的系统，具有可复制和定义的架构、大小和细胞组成。重新布线蜂窝网络将引导细胞自主地对其微环境做出反应。这些细胞将复制模板早期皮质生成，同时在后期平衡祖细胞的增殖和分化。已发现的原理将指导利用大脑有机化合物来了解发育和疾病，并筛选潜在的治疗方法。理解控制大脑中更高层次结构形成的设计规则可能会应用于其他类型的组织。这进一步打开了用于移植的工程组织替代的可能性。该项目由ENG/CBET中的工程生物学和健康集群以及BIO/MCB中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。

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.