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
基本信息
- 批准号:10361499
- 负责人:
- 金额:$ 116.65万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:22q1122q11.2AKT Signaling PathwayAKT1 geneAdultAffectAnatomyAnimal ModelArchitectureBiologicalBlood - brain barrier anatomyBlood VesselsBrainCardiovascular systemCategoriesCell LineCerebrumClustered Regularly Interspaced Short Palindromic RepeatsCoupledDevelopmentDiGeorge SyndromeDiseaseDisease modelDrug ScreeningDrug TargetingElectrophysiology (science)Endonuclease IEpilepsyFailureFunctional disorderGenerationsGenesGeneticGrowthHumanImpairmentIncidenceInflammationIntellectual functioning disabilityInvestigationInvestmentsLesionLifeLinkLive BirthMeasuresMicrofluidic MicrochipsModelingMolecularMutationNational Institute of Mental HealthNerveNervous System PhysiologyNeuraxisNeuronsOnline Mendelian Inheritance In ManOrganoidsOxygenPI3K/AKTPathway interactionsPatientsPatternPharmaceutical PreparationsPharmacologic SubstancePhasePhysiologicalPlayPrincipal InvestigatorProcessProteus SyndromePublic HealthResearch PersonnelRoleSamplingSchizophreniaSecureSignal PathwayStressStructureSyndromeSystemSystems DevelopmentTechniquesTissue EngineeringTissuesValidationVascular Endothelial Growth FactorsVascular SystemVasoconstrictor AgentsVasodilator Agentsautism spectrum disorderbaseblood-brain barrier permeabilizationbrain tissuecell bankclinical developmentclinical phenotypedisabilitydisease phenotypedrug developmentdruggable targethigh riskhuman tissueimprovedinduced pluripotent stem cellinjury and repairmicrophysiology systemneural networkneuroimagingneuropsychiatric disorderneuropsychiatrynovelpreventprogramsrelating to nervous systemresponsesolutestem cellssuccesstreatment strategyvascular abnormality
项目摘要
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,对精神科药物开发的投资。局限性
与动物模型和缺乏可药物生物靶标有关,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,形成大脑微生理
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。
项目成果
期刊论文数量(17)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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:
- 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.
- DOI:10.1016/j.copbio.2020.06.009
- 发表时间:2020-12
- 期刊:
- 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:
- 影响因子:6
- 作者:
- 通讯作者:
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:
- 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
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:
- 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
- 通讯作者: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
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
KAM W LEONG其他文献
KAM W LEONG的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('KAM W LEONG', 18)}}的其他基金
Focused Ultrasound-mediated Delivery of Gene-editing Elements to the Brain for Neurodegenerative Disorders
聚焦超声介导的基因编辑元件递送至大脑以治疗神经退行性疾病
- 批准号:
9810901 - 财政年份:2019
- 资助金额:
$ 116.65万 - 项目类别:
Evaluation of nonviral gene editing systems in the brain assisted by focused ultrasound
聚焦超声辅助下大脑非病毒基因编辑系统的评估
- 批准号:
10658371 - 财政年份:2019
- 资助金额:
$ 116.65万 - 项目类别:
Focused Ultrasound-mediated Delivery of Gene-editing Elements to the Brain for Neurodegenerative Disorders
聚焦超声介导的基因编辑元件递送至大脑以治疗神经退行性疾病
- 批准号:
10248386 - 财政年份:2019
- 资助金额:
$ 116.65万 - 项目类别:
Focused Ultrasound-mediated Delivery of Gene-editing Elements to the Brain for Neurodegenerative Disorders
聚焦超声介导的基因编辑元件递送至大脑以治疗神经退行性疾病
- 批准号:
10619032 - 财政年份:2019
- 资助金额:
$ 116.65万 - 项目类别:
Engineering Polymers to Scavenge DAMPs in Arthritis and Lupus
工程聚合物可清除关节炎和狼疮中的 DAMP
- 批准号:
9761982 - 财政年份:2018
- 资助金额:
$ 116.65万 - 项目类别:
Engineering Polymers to Scavenge DAMPs in Arthritis and Lupus
工程聚合物可清除关节炎和狼疮中的 DAMP
- 批准号:
10470805 - 财政年份:2018
- 资助金额:
$ 116.65万 - 项目类别:
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:
10055998 - 财政年份:2018
- 资助金额:
$ 116.65万 - 项目类别:
Engineering Polymers to Scavenge DAMPs in Arthritis and Lupus
工程聚合物可清除关节炎和狼疮中的 DAMP
- 批准号:
10220851 - 财政年份:2018
- 资助金额:
$ 116.65万 - 项目类别:
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 - 财政年份:2018
- 资助金额:
$ 116.65万 - 项目类别:
Engineering Polymers to Scavenge DAMPs in Arthritis and Lupus
工程聚合物可清除关节炎和狼疮中的 DAMP
- 批准号:
9979764 - 财政年份:2018
- 资助金额:
$ 116.65万 - 项目类别:
相似国自然基金
22q11.2微缺失综合症中T盒转录因子Tbx1与信号接头蛋白Crkl遗传相互作用致肺动脉发育不良缺陷的机制研究
- 批准号:81170153
- 批准年份:2011
- 资助金额:60.0 万元
- 项目类别:面上项目
基于染色体22q11.2候选基因与腭心面综合征表型的分子诊断研究
- 批准号:81070813
- 批准年份:2010
- 资助金额:35.0 万元
- 项目类别:面上项目
无22q11.2区基因微缺失的心脏圆锥动脉干畸形患者中新TBX1突变体蛋白的功能研究
- 批准号:81070135
- 批准年份:2010
- 资助金额:32.0 万元
- 项目类别:面上项目
染色体22q11.2区域泌尿系统畸形关键致病基因的克隆与鉴定
- 批准号:30571867
- 批准年份:2005
- 资助金额:25.0 万元
- 项目类别:面上项目
相似海外基金
成人期へtransitionする22q11.2欠失症候群患者の移行支援プログラムの構築
为 22q11.2 缺失综合征患者过渡到成年期建立过渡支持计划
- 批准号:
24K13915 - 财政年份:2024
- 资助金额:
$ 116.65万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
An Engineered Hydrogel Platform to Improve Neural Organoid Reproducibility for a Multi-Organoid Disease Model of 22q11.2 Deletion Syndrome
一种工程水凝胶平台,可提高 22q11.2 缺失综合征多器官疾病模型的神经类器官再现性
- 批准号:
10679749 - 财政年份:2023
- 资助金额:
$ 116.65万 - 项目类别:
重複障害を呈する医療的ケア児と家族の移行期における意思決定支援のPPI型研究
多重残疾儿童及其家庭过渡期决策支持的PPI型研究
- 批准号:
23H02834 - 财政年份:2023
- 资助金额:
$ 116.65万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Outcomes and disease burden in a model of young adult multimorbidity
年轻成人多重病模型的结果和疾病负担
- 批准号:
479042 - 财政年份:2023
- 资助金额:
$ 116.65万 - 项目类别:
Operating Grants
22q11.2欠失症候群との網羅的な比較検討によるファロー四徴症での遺伝子異常の解明
与22q11.2缺失综合征综合比较阐明法洛四联症遗传异常
- 批准号:
23K08237 - 财政年份:2023
- 资助金额:
$ 116.65万 - 项目类别:
Grant-in-Aid for Scientific Research (C)