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: 10174287
• 负责人: KEVIN C ESS
• 金额: $ 114.29万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10174287
• 关键词: 2019-nCoV; Acute; Address; Affect; Air; Anti-Inflammatory Agents; Antiviral Agents; Benchmarking; Biological Models; Blood - brain barrier anatomy; Blood Vessels; Brain; CD14 gene; COVID-19; Cardiac; Cells; Central Nervous System Infections; Cessation of life; Childhood; Clinical; Communicable Diseases; Coronavirus; Coupled; Coupling; Dendritic Cells; Disease; Disease Progression; Disease model; Drug Screening; Education; Endothelial Cells; Environment; Epilepsy; Epithelial Cells; FDA approved; Force of Gravity; Functional disorder; Goals; Human; Immune; Immune response; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Innate Immune System; Institutes; Liquid substance; Lung; Lung Inflammation; Lung diseases; Measurement; Modeling; Neuraxis; Organ; Outcome; Pathologic; Patients; Perfusion; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacotherapy; Phase; Physiological; Play; Pneumonia; Production; Publishing; Reporting; Research; Respiratory Failure; Respiratory System; Respiratory Tract Infections; Role; Sampling; Seeds; Solvents; Symptoms; System; Techniques; Testing; Therapeutic; Therapeutic Agents; Tissue Microarray; Tissues; Treatment Efficacy; Tuberous sclerosis protein complex; Tunica Media; Universities; Viral; Virus; Virus Diseases; airway epithelium; base; biodefense; biosafety level 3 facility; body system; bronchial epithelium; cell type; cytokine; cytokine release syndrome; drug development; drug efficacy; drug testing; effective therapy; experimental study; hospitalization rates; improved; innate immune function; macrophage; metabolomics; microphysiology system; monolayer; mortality; neurovascular; neurovascular unit; pandemic disease; prevent; recruit; response; screening; therapeutic evaluation; treatment strategy

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