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Determinants of COVID19-induced venous thrombosis and targeted therapy assessed with bioengineered vein-chip

用生物工程静脉芯片评估新冠病毒引起的静脉血栓形成的决定因素和靶向治疗

基本信息

批准号：
10617651
负责人：
JOHN P COOKE
金额：
$ 73.23万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10617651
关键词：
2019-nCoV ACE2 Address Adhesions American Anticoagulants Anticoagulation Apoptosis Attention Attenuated Automobile Driving Autopsy Biological Assay Biomedical Engineering Blood Blood Vessels Blood coagulation COVID-19 COVID-19 patient COVID-19 treatment Cells Cessation of life China Clinical Research Complex Computational Biology Data Deep Vein Thrombosis Development Devices Disease Distal Endothelial Cells Endothelium Enzyme Inhibitor Drugs Exposure to Geometry Homeostasis Human Immune response Infection Inflammation Inflammatory Interdisciplinary Study Kidney Lead Life Lower Extremity Lung Mesentery Modeling Molecular Biology NF-kappa B Organ Outcome Pathway interactions Patients Persons Pharmaceutical Preparations Physiological Play Pre-Clinical Model Predisposition Proteins Proteomics Research Respiratory Failure Role SARS-CoV-2 infection Signal Pathway Stroke Structure Surgeon Techniques Technology Therapeutic Therapeutic Clinical Trial Thrombosis Veins Venous Venous Thrombosis Viral Virus Virus Diseases clinical phenotype combinatorial cytokine design differential expression efficacy evaluation endothelial dysfunction hemodynamics improved innovation mechanotransduction mortality novel novel coronavirus organ on a chip prevent receptor recruit response severe COVID-19 targeted treatment thromboinflammation transcriptome transcriptome sequencing venous thromboembolism

项目摘要

ABSTRACT Determinants of COVID19-induced venous thrombosis and targeted therapy assessed with bioengineered Vein-Chip Challenge: Increasing evidence shows that SARS-CoV-2, which is the novel coronavirus that causes COVID- 19, is able to trigger the formation of blood clots within the veins of patients. This ultimately manifests into strokes and other life-threatening complications, being observed even in younger people. Related to that, is emerging data that shows that the endothelial cells are dysfunctional across several organs other than the lungs of the most severe COVID19 patients. These cells express the angiotensin-converting enzyme 2 (ACE2) receptor, to which the virus attaches, using it as an entry point to infect cells. A recently created vein-on-a-chip (vein-chip) that is an endothelialized organ-on-a-chip model incorporating the unique hemodynamics of the venous valve cusp showed evidence that this model can be used to dissect the role of major determinants of venous thrombosis – endothelium; hemodynamics; and blood components – together known as the Virchow's triad. The central hypothesis in this proposal is that the venous thrombosis observed in COVID19 disease is due to the interaction of the three determinants of thrombosis (Virchow's triad) – endotheliitis; complex hemodynamics; and blood coagulability. There is an unmet need to understand the effects of the virus and/or blood-borne inflammatory cytokines on the endothelium; and the interaction of these effects with the uniquely complex venous hemodynamics (mechanotransduction); and to discover strategies to stabilize the endothelium that may be co-operatively therapeutic with anticoagulants. Proposal: The objective here is to deploy vein-chip technology to understand the determinants of SARS-CoV- 2 induced venous thrombosis; determine the roles of endothelial, hemodynamic and humoral alterations; and propose therapeutic strategies. This objective will be met through three specific aims: Aim 1: Characterize the SARS-CoV-2 induced endothelial dysfunction in the human Vein-Chip; Aim 2: Assess interplay of SARS-CoV-2 infection and hemodynamics in DVT with Vein-Chip, and Aim 3: Therapeutics-on-Chip: Assess combinatorial therapeutics in infection-led DVT with Vein-Chip. The team driving this proposal is composed of complementary expertise in vein-chip bioengineering and innovation (Jain); applying contemporary technology in the molecular and computational biology of endothelial function and fate (Cooke); together with techniques to define host response to coronaviral infection (Connor). Impact: Taken together, the outcomes of this proposal will directly improve our understanding of thrombosis in COVID-19 infection and make predictions that could potentially result in fast-tracking of therapeutic clinical trials.

摘要