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: 10361499
• 负责人: KAM W LEONG
• 金额: $ 116.65万
• 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 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10361499
• 关键词: 22q11; 22q11.2; AKT Signaling Pathway; AKT1 gene; Adult; Affect; Anatomy; Animal Model; Architecture; Biological; 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; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Physiological; Play; Principal Investigator; Process; Proteus Syndrome; Public Health; Research Personnel; Role; Sampling; Schizophrenia; Secure; Signal Pathway; Stress; Structure; Syndrome; System; Systems Development; Techniques; Tissue Engineering; Tissues; Validation; Vascular Endothelial Growth Factors; Vascular System; Vasoconstrictor Agents; Vasodilator Agents; autism spectrum disorder; base; blood-brain barrier permeabilization; brain tissue; cell bank; clinical development; clinical phenotype; disability; disease phenotype; drug development; druggable target; high risk; human tissue; improved; induced pluripotent stem cell; injury and repair; microphysiology system; neural network; neuroimaging; neuropsychiatric disorder; neuropsychiatry; novel; prevent; programs; relating to nervous system; response; solute; stem cells; 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.

摘要

项目成果

High-Throughput Tumor-on-a-Chip Platform to Study Tumor-Stroma Interactions and Drug Pharmacokinetics.

• DOI: 10.1002/adhm.202000880
• 发表时间: 2020-11
• 期刊: Advanced healthcare materials
• 影响因子: 10
• 作者: Chi CW;Lao YH;Ahmed AHR;Benoy EC;Li C;Dereli-Korkut Z;Fu BM;Leong KW;Wang S
• 通讯作者: Wang S

Advances in microphysiological blood-brain barrier (BBB) models towards drug delivery.

微生物生理学血脑屏障（BBB）模型的进展促进药物输送。

• DOI: 10.1016/j.copbio.2020.06.009
• 发表时间: 2020-12
• 期刊: Current opinion in biotechnology
• 影响因子: 7.7
• 作者: Lee CS;Leong KW
• 通讯作者: Leong KW

Inhibition of Abl Kinase by Imatinib Can Rescue the Compromised Barrier Function of 22q11.2DS Patient-iPSC-Derived Blood-Brain Barriers.

• DOI: 10.3390/cells12030422
• 发表时间: 2023-01-27
• 期刊: Cells
• 影响因子: 6

Targeting Proinflammatory Molecules Using Multifunctional MnO Nanoparticles to Inhibit Breast Cancer Recurrence and Metastasis.

• DOI: 10.1021/acsnano.2c06713
• 发表时间: 2022-11
• 期刊: ACS nano
• 影响因子: 17.1
• 作者: Yiling Zhong;Tianyu Li;Yuefei Zhu;Jiehau Zhou;Tolulope Akinade;Jounghyun H Lee;Feng Liu;Divya Bhansali;Yeh-Hsing Lao;C. Quek;Dan Shao;Kam W. Leong

Spatial profiling of chromatin accessibility in mouse and human tissues.

• DOI: 10.1038/s41586-022-05094-1
• 发表时间: 2022-09
• 期刊: NATURE
• 影响因子: 64.8
• 作者: Deng, Yanxiang;Bartosovic, Marek;Ma, Sai;Zhang, Di;Kukanja, Petra;Xiao, Yang;Su, Graham;Liu, Yang;Qin, Xiaoyu;Rosoklija, Gorazd B.;Dwork, Andrew J.;Mann, J. John;Xu, Mina L.;Halene, Stephanie;Craft, Joseph E.;Leong, Kam W.;Boldrini, Maura;Castelo-Branco, Goncalo;Fan, Rong
• 通讯作者: Fan, Rong