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。的 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。尽管面临挑战，但针对这些疾病的药物开发 疾病正面临危机;大多数主要制药公司已经减少了他们的 因为失败率很高。限制 与动物模型和缺乏可药物化的生物靶点相关， 很难接触到活的人脑进行动态观察和实验， 共同构成了寻找有效精神药物的巨大挑战。最近 人类诱导性多能干细胞（hiPSC）的进展使得有可能 产生患者特异性脑样神经组织（称为“脑类器官”）， 显示出类似于人体组织的结构和神经网络活动。 这些脑类器官（CO）为研究人员提供了一个令人兴奋的机会， 疾病机制负责发展的神经精神障碍， 人类我们在这个项目中提出将CO与组织工程血管（BV）连接起来 和它们的血脑屏障（BBB）界面形成脑微生理 CMPS系统。有文献记载血管和神经之间的解剖学平行性 模式和发展，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。的 相同的信号传导通路也在神经之间的串扰中起关键作用， 在成年人脑损伤修复过程中的血管。因此， 了解CNS和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 遗传性病变，22q11.2缺失综合征（22q11.2DS或DiGeorge综合征）和 变形综合征，影响中枢神经系统和血管系统， CMPS的开发和验证。建议的综合医疗保障计划如能成功推行， 强大的平台来筛选神经精神药物以及开发新的 神经精神治疗策略，目标之间的共享机制， CNS和血管系统。 !

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. !