Integrated Microphysiological System of Cerebral Organoid and Blood Vessel for Disease Modeling and Neuropsychiatric Drug screening

摘要 许多神经精神障碍，如自闭症、癫痫、精神分裂症和 智力残疾在生命早期就开始了，往往会导致终生残疾。这个 这些疾病发病率的上升预计将造成重大的公共卫生挑战 在未来的几十年里。尽管面临着迫在眉睫的挑战，但这些国家的药物开发 疾病正面临危机；大多数主要制药公司已经减少了他们的 由于失败率高，对精神药物开发的投资。局限性 与动物模型和缺乏可用药的生物靶点有关，再加上 很难接触到活着的人脑进行动态观察和实验 合谋对寻找有效的精神药物施加巨大挑战。近期 人类诱导多能干细胞(HiPSC)的研究进展使其成为可能 创建一种特定于患者的类脑神经组织(称为‘脑器官’)，它 展示了一种类似于人体组织的结构和神经网络活动。 这些脑有机体(CO)为研究人员提供了一个令人兴奋的机会 神经精神障碍发展的疾病机制 人类。在这个项目中，我们建议将一氧化碳与组织工程血管(BV)联系起来 和它们的血脑屏障(BBB)界面形成脑微生理学 系统(CMPS)。已有文献证明血管和神经在解剖上是平行的。 图案化和发育，也出现了神经元和血管 规格、生长、导航和生存共享许多分子途径。这个 同样的信号通路也在神经和神经之间的串扰中起着关键作用 成人脑损伤修复过程中的血管。因此，重要的是要 了解中枢神经系统与血管系统之间的相互作用 生理和病理生理条件。我们建议使用两个定义明确的 遗传损害、22q11.2缺失综合征(22q11.2DS或DiGeorge综合征)和 Proteus综合征，影响中枢和血管系统的 中药的开发和验证。拟议的中医如果成功，将提供一个 筛选神经精神药物以及开发新药物的强大平台 神经精神病学治疗策略，针对的是 中枢神经系统和血管系统。 好了！

Abstract Many neuropsychiatric disorders such as autism, epilepsy, schizophrenia, and intellectual disability start early in life and often contribute to a lifetime disability. The rising incidence of these disorders is expected to cause a major public health challenge in the coming decades. Despite the impending challenge, drug development for these disorders is facing a crisis; most major pharmaceutical companies have reduced their investment in psychiatric drug development because of a high failure rate. Limitations associated with animal models and a dearth of druggable biological targets, coupled with poor access to the living human brain for dynamic observation and experimentation all conspire to impose an enormous challenge of finding effective psychiatric drugs. Recent advances in human induced pluripotent stem cells (hiPSC) have made it possible to create a patient-specific brain-like neural tissue (referred to as `cerebral organoid') that displays an architecture and neural network activity resembling that of human tissue. These cerebral organoids (CO) offer researchers an exciting opportunity to investigate disease mechanisms responsible for the development of neuropsychiatric disorders in humans. We propose in this project to link CO with a tissue-engineered blood vessel (BV) and their blood-brain barrier (BBB) interface to form a cerebral microphysiological system (CMPS). There is documented anatomical parallelism between vessel and nerve patterning and development, and it has also emerged that neuron and vessel specification, growth, navigation, and survival share many molecular pathways. The same signaling pathways also play a critical role in the crosstalk between nerves and vessels during the injury repair process in adult brain. Therefore, it is important to understand the interactions between the CNS and the vascular system under physiological and pathophysiological conditions. We propose to use two well-defined genetic lesions, the 22q11.2 deletion syndrome (22q11.2DS or DiGeorge syndrome) and the Proteus syndrome, that affect both the CNS and vascular systems for the development and validation of CMPS. The proposed CMPS, if successful, will offer a powerful platform to screen neuropsychiatric drugs as well as to develop novel neuropsychiatric treatment strategies that target the shared mechanisms between the CNS and the vascular system. !