Drug development for tuberous sclerosis complex and other pediatric epileptogenic diseases using neurovascular and cardiac microphysiological models
使用神经血管和心脏微生理学模型开发结节性硬化症和其他儿科癫痫性疾病的药物
基本信息
- 批准号:10174287
- 负责人:
- 金额:$ 114.29万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-09-19 至 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:2019-nCoVAcuteAddressAffectAirAnti-Inflammatory AgentsAntiviral AgentsBenchmarkingBiological ModelsBlood - brain barrier anatomyBlood VesselsBrainCD14 geneCOVID-19CardiacCellsCentral Nervous System InfectionsCessation of lifeChildhoodClinicalCommunicable DiseasesCoronavirusCoupledCouplingDendritic CellsDiseaseDisease ProgressionDisease modelDrug ScreeningEducationEndothelial CellsEnvironmentEpilepsyEpithelial CellsFDA approvedForce of GravityFunctional disorderGoalsHumanImmuneImmune responseIn VitroInfectionInflammationInflammatoryInflammatory ResponseInnate Immune SystemInstitutesLiquid substanceLungLung InflammationLung diseasesMeasurementModelingNeuraxisOrganOutcomePathologicPatientsPerfusionPeripheral Blood Mononuclear CellPharmaceutical PreparationsPharmacotherapyPhasePhysiologicalPlayPneumoniaProductionPublishingReportingResearchRespiratory FailureRespiratory SystemRespiratory Tract InfectionsRoleSamplingSeedsSolventsSymptomsSystemTechniquesTestingTherapeuticTherapeutic AgentsTissue MicroarrayTissuesTreatment EfficacyTuberous sclerosis protein complexTunica MediaUniversitiesViralVirusVirus Diseasesairway epitheliumbasebiodefensebiosafety level 3 facilitybody systembronchial epitheliumcell typecytokinecytokine release syndromedrug developmentdrug efficacydrug testingeffective therapyexperimental studyhospitalization ratesimprovedinnate immune functionmacrophagemetabolomicsmicrophysiology systemmonolayermortalityneurovascularneurovascular unitpandemic diseasepreventrecruitresponsescreeningtherapeutic evaluationtreatment strategy
项目摘要
Although COVID-19 is recognized primarily as a respiratory infection and the majority of deaths from the
disease are attributed to pulmonary failure, it has become increasingly apparent that the SARS-CoV-2 virus,
either directly or indirectly, affects all major organ systems with a confounding degree of variability that
complicates the identification of effective therapeutics. In particular, the central nervous system (CNS) and
vasculature both seem to play a significant role in disease progression, and CNS symptoms have correlated
with poorer outcomes in COVID-19 patients. It is hypothesized that the CNS and vasculature each influence
pathological dysregulation of immune response, but very little is known about how they respond and possibly
contribute to disease progression. No single therapeutic agent has emerged that broadly neutralizes COVID-19
disease progression, which strongly suggests that any effective treatment strategies will need to address not
only effects of SARS-CoV-2 infection in the lungs, but also inflammation in many organ systems, which in turn
would require therapeutic access to the CNS. Thus, understanding the interactions between the lungs and the
CNS is critical to identifying treatments capable of improving the prognoses of COVID-19 patients and reducing
hospitalization rates and mortality. This project will evaluate how SARS-CoV-2 infection in the lungs
contributes to both the organ dysfunction in COVID-19 and potential CNS infection, and how well the
combination of anti-viral and anti-inflammatory drugs addresses CNS involvement in COVID-19. These goals
demand a physiologically relevant in vitro platform that fully recapitulates the systemic immune and cytokine
storm responses following infection of airway epithelium associated with the most severe cases of COVID-19
and that can be readily used in the Biosafety Level-3 (BSL-3) facilities required for studies of this highly
infectious respiratory disease. This project will implement a two-organ microphysiological system (MPS) model
that uses an existing NeuroVascular Unit (NVU)/blood-brain barrier tissue chip for the CNS component,
repurposes the NVU as an Airway Chip for the lung component, and converts both chips to gravity perfusion
for ease of use in BSL-3 facilities. The aims are to 1) model COVID-19 infection and innate pulmonary
response in the Airway Chip, 2) couple the NVU and Airway Chip to evaluate how the response of the Airway
Chip to COVID-19 infection affects the function of the NVU, as required to establish therapeutic benchmarks
for drug testing, and 3) screen FDA-approved drugs for efficacy in treating negative symptoms in the
NVU/Airway Chip model. A comparison of infection of the separate NVU/CNS and Airway tissue chips with
infection of the coupled-chip system will help determine the infectability of each MPS model and the viral
capacity to cross the blood-brain barrier into the CNS. Candidate FDA-approved drugs will be tested for their
ability to affect viral infection, replication, and cytokine production in both microphysiological systems.
虽然COVID-19主要被认为是一种呼吸道感染,但大多数死亡来自于
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(6)
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KEVIN C ESS其他文献
KEVIN C ESS的其他文献
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{{ truncateString('KEVIN C ESS', 18)}}的其他基金
Identifying mTOR Dependent Periods During Brain Development
识别大脑发育过程中 mTOR 依赖期
- 批准号:
10352829 - 财政年份:2021
- 资助金额:
$ 114.29万 - 项目类别:
Identifying mTOR Dependent Periods During Brain Development
识别大脑发育过程中 mTOR 依赖期
- 批准号:
10442566 - 财政年份:2020
- 资助金额:
$ 114.29万 - 项目类别:
Identifying mTOR Dependent Periods During Brain Development
识别大脑发育过程中 mTOR 依赖期
- 批准号:
10054882 - 财政年份:2020
- 资助金额:
$ 114.29万 - 项目类别:
Identifying mTOR Dependent Periods During Brain Development
识别大脑发育过程中 mTOR 依赖期
- 批准号:
10240722 - 财政年份:2020
- 资助金额:
$ 114.29万 - 项目类别:
Identifying mTOR Dependent Periods During Brain Development
识别大脑发育过程中 mTOR 依赖期
- 批准号:
10653864 - 财政年份:2020
- 资助金额:
$ 114.29万 - 项目类别:
Drug development for tuberous sclerosis complex and other pediatric epileptogenic diseases using neurovascular and cardiac microphysiological models
使用神经血管和心脏微生理学模型开发结节性硬化症和其他儿科癫痫性疾病的药物
- 批准号:
10240589 - 财政年份:2017
- 资助金额:
$ 114.29万 - 项目类别:
Regulation of Neurogenesis in TSC by mTORC1 and mTORC2
mTORC1 和 mTORC2 对 TSC 神经发生的调节
- 批准号:
8658864 - 财政年份:2012
- 资助金额:
$ 114.29万 - 项目类别:
Regulation of Neurogenesis in TSC by mTORC1 and mTORC2
mTORC1 和 mTORC2 对 TSC 神经发生的调节
- 批准号:
8473929 - 财政年份:2012
- 资助金额:
$ 114.29万 - 项目类别:
Regulation of Neurogenesis in TSC by mTORC1 and mTORC2
mTORC1 和 mTORC2 对 TSC 神经发生的调节
- 批准号:
8399444 - 财政年份:2012
- 资助金额:
$ 114.29万 - 项目类别:
The Role of TSC Genes During Brain Development
TSC 基因在大脑发育过程中的作用
- 批准号:
8075009 - 财政年份:2007
- 资助金额:
$ 114.29万 - 项目类别:
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