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

用于疾病建模和神经精神药物筛选的脑类器官和血管的集成微生理系统

• 批准号: 9401926
• 负责人: KAM W LEONG
• 金额: $ 117.71万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-15 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9401926
• 关键词: 22q11; 22q11 Deletion Syndrome; 22q11.2; AKT Signaling Pathway; AKT1 gene; Adult; Affect; Anatomy; Animal Model; Architecture; Autistic Disorder; Biological; Biological Neural Networks; Blood - brain barrier anatomy; Blood Vessels; Brain; Cardiovascular system; Categories; Cell Line; Cerebrum; Clustered Regularly Interspaced Short Palindromic Repeats; Coupled; Development; DiGeorge Syndrome; Disease; Disease model; Drug Screening; Drug Targeting; Electrophysiology (science); Endonuclease I; Epilepsy; Failure; Functional disorder; Generations; Genes; Genetic; Growth; Human; Impairment; Incidence; Inflammation; Intellectual functioning disability; Investigation; Investments; Lesion; Life; Link; Live Birth; Measures; Microfluidic Microchips; Modeling; Molecular; Mutation; National Institute of Mental Health; Nerve; Nervous System Physiology; Neuraxis; Neurons; Online Mendelian Inheritance In Man; Organoids; Oxygen; PI3K/AKT; Pathway interactions; Patients; Pattern; Permeability; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Physiological; Play; Principal Investigator; Process; Proteus Syndrome; Public Health; Research Personnel; Role; Sampling; Schizophrenia; Secure; Signal Pathway; Stem cells; Stress; Structure; Syndrome; System; Systems Development; Techniques; Tissue Engineering; Tissues; Validation; Vascular Endothelial Growth Factors; Vascular System; Vasoconstrictor Agents; Vasodilator Agents; base; brain tissue; cell bank; clinical development; clinical phenotype; conotruncal anomaly face syndrome; disability; disease phenotype; drug development; druggable target; high risk; human tissue; improved; induced pluripotent stem cell; injury and repair; microphysiology system; neuroimaging; neuropsychiatric disorder; neuropsychiatry; novel; prevent; programs; relating to nervous system; response; solute; success; treatment strategy; vascular abnormality

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. !

抽象的 许多神经精神疾病，如自闭症、癫痫、精神分裂症等 智力障碍始于生命早期，并常常导致终生残疾。这 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。尽管面临迫在眉睫的挑战，但这些药物的开发 疾病正面临危机；大多数主要制药公司都减少了 由于失败率高，对精神科药物开发进行了投资。局限性 与动物模型和缺乏可药物生物靶点有关，再加上 很难接近活人大脑进行动态观察和实验 合谋对寻找有效的精神治疗药物提出了巨大的挑战。最近的 人类诱导多能干细胞（hiPSC）的进步使得 创建患者特异性的类脑神经组织（称为“大脑类器官”） 显示类似于人体组织的架构和神经网络活动。 这些大脑类器官（CO）为研究人员提供了一个令人兴奋的研究机会 导致神经精神疾病发展的疾病机制 人类。我们在这个项目中建议将 CO 与组织工程血管 (BV) 连接起来 及其血脑屏障（BBB）界面，形成脑微生理 系统（CMPS）。有记录表明血管和神经之间存在解剖学上的平行性 模式和发育，并且还发现神经元和血管 规范、生长、导航和生存共享许多分子途径。这 同样的信号通路在神经和神经之间的串扰中也发挥着关键作用。 成人大脑损伤修复过程中的血管。因此，重要的是 了解中枢神经系统和血管系统之间的相互作用 生理和病理生理条件。我们建议使用两个明确定义的 遗传病变、22q11.2 缺失综合征（22q11.2DS 或 DiGeorge 综合征）和 Proteus 综合征，影响中枢神经系统和血管系统 CMPS 的开发和验证。拟议的 CMPS 如果成功，将提供 筛选神经精神药物以及开发新型药物的强大平台 针对神经精神病学之间共享机制的治疗策略 中枢神经系统和血管系统。 ！