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.
尽管COVID-19主要被认为是一种呼吸道感染,
疾病归因于肺衰竭,越来越明显的是SARS-CoV-2病毒,
直接或间接地影响所有主要器官系统,具有混杂程度的变异性,
使有效治疗剂的鉴定复杂化。特别是中枢神经系统(CNS)和
血管系统似乎在疾病进展中起重要作用,CNS症状与疾病进展相关。
在COVID-19患者中的结果较差。假设中枢神经系统和血管系统各自影响
免疫反应的病理性失调,但对它们如何反应知之甚少,
有助于疾病进展。目前还没有出现一种能广泛中和COVID-19的治疗药物
疾病进展,这强烈表明,任何有效的治疗策略都需要解决不
只有SARS-CoV-2感染在肺部的影响,而且在许多器官系统中也有炎症,
需要进入中枢神经系统进行治疗因此,了解肺和肺之间的相互作用,
CNS对于确定能够改善COVID-19患者病情并减少
住院率和死亡率。该项目将评估SARS-CoV-2如何在肺部感染
导致COVID-19中的器官功能障碍和潜在的CNS感染,
抗病毒和抗炎药物的组合解决了CNS参与COVID-19的问题。这些目标
需要一种生理学相关的体外平台,其完全概括全身免疫和细胞因子
与最严重的COVID-19病例相关的气道上皮感染后的风暴反应
并且可以很容易地用于生物安全3级(BSL-3)设施,用于研究这种高度生物安全的生物。
传染性呼吸道疾病本计画将实作一个双器官微生理系统(MPS)模型
它使用现有的神经血管单元(NVU)/血脑屏障组织芯片作为CNS组件,
将NVU重新用作肺部组件的气道芯片,并将两种芯片转换为重力灌注
以便于在BSL-3设施中使用。目的是1)模拟COVID-19感染和先天性肺
2)将NVU与气道芯片耦合以评估气道芯片的响应如何与NVU的响应相关联,
根据建立治疗基准的要求,COVID-19感染的芯片会影响NVU的功能
进行药物测试,3)筛选FDA批准的药物,以确定其治疗阴性症状的有效性。
NVU/气道芯片型号。比较单独的NVU/CNS和气道组织芯片的感染,
耦合芯片系统的感染将有助于确定每个MPS模型和病毒的感染性,
穿过血脑屏障进入中枢神经系统的能力。FDA批准的候选药物将被测试其
在两种微生理系统中影响病毒感染、复制和细胞因子产生的能力。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
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 }}
KEVIN C ESS其他文献
KEVIN C ESS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('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:
相似海外基金
Acute senescence: a novel host defence counteracting typhoidal Salmonella
急性衰老:对抗伤寒沙门氏菌的新型宿主防御
- 批准号:
MR/X02329X/1 - 财政年份:2024
- 资助金额:
$ 114.29万 - 项目类别:
Fellowship
Transcriptional assessment of haematopoietic differentiation to risk-stratify acute lymphoblastic leukaemia
造血分化的转录评估对急性淋巴细胞白血病的风险分层
- 批准号:
MR/Y009568/1 - 财政年份:2024
- 资助金额:
$ 114.29万 - 项目类别:
Fellowship
Combining two unique AI platforms for the discovery of novel genetic therapeutic targets & preclinical validation of synthetic biomolecules to treat Acute myeloid leukaemia (AML).
结合两个独特的人工智能平台来发现新的基因治疗靶点
- 批准号:
10090332 - 财政年份:2024
- 资助金额:
$ 114.29万 - 项目类别:
Collaborative R&D
Cellular Neuroinflammation in Acute Brain Injury
急性脑损伤中的细胞神经炎症
- 批准号:
MR/X021882/1 - 财政年份:2024
- 资助金额:
$ 114.29万 - 项目类别:
Research Grant
STTR Phase I: Non-invasive focused ultrasound treatment to modulate the immune system for acute and chronic kidney rejection
STTR 第一期:非侵入性聚焦超声治疗调节免疫系统以治疗急性和慢性肾排斥
- 批准号:
2312694 - 财政年份:2024
- 资助金额:
$ 114.29万 - 项目类别:
Standard Grant
Combining Mechanistic Modelling with Machine Learning for Diagnosis of Acute Respiratory Distress Syndrome
机械建模与机器学习相结合诊断急性呼吸窘迫综合征
- 批准号:
EP/Y003527/1 - 财政年份:2024
- 资助金额:
$ 114.29万 - 项目类别:
Research Grant
FITEAML: Functional Interrogation of Transposable Elements in Acute Myeloid Leukaemia
FITEAML:急性髓系白血病转座元件的功能研究
- 批准号:
EP/Y030338/1 - 财政年份:2024
- 资助金额:
$ 114.29万 - 项目类别:
Research Grant
KAT2A PROTACs targetting the differentiation of blasts and leukemic stem cells for the treatment of Acute Myeloid Leukaemia
KAT2A PROTAC 靶向原始细胞和白血病干细胞的分化,用于治疗急性髓系白血病
- 批准号:
MR/X029557/1 - 财政年份:2024
- 资助金额:
$ 114.29万 - 项目类别:
Research Grant
ロボット支援肝切除術は真に低侵襲なのか?acute phaseに着目して
机器人辅助肝切除术真的是微创吗?
- 批准号:
24K19395 - 财政年份:2024
- 资助金额:
$ 114.29万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Collaborative Research: Changes and Impact of Right Ventricle Viscoelasticity Under Acute Stress and Chronic Pulmonary Hypertension
合作研究:急性应激和慢性肺动脉高压下右心室粘弹性的变化和影响
- 批准号:
2244994 - 财政年份:2023
- 资助金额:
$ 114.29万 - 项目类别:
Standard Grant