High-throughput Imaging-integrated Vascular Model for Understanding Thromboembolism and Therapeutics Screening

用于了解血栓栓塞和治疗筛选的高通量成像集成血管模型

基本信息

批准号：
10564808
负责人：
Junjie Yao
金额：
$ 63.59万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10564808
关键词：
2019-nCoV 3-Dimensional Acute Adopted Affect Alteplase Animal Model Anticoagulation Antiviral Agents Arteries Behavior monitoring Blood Vessels Blood flow COVID-19 assay Capital Cardiovascular Diseases Cardiovascular system Cell Culture Techniques Cells Cessation of life Clinical Coagulation Process Collagen Type I Complement Deep Vein Thrombosis Development Disease Drug Screening Edema Endothelium Engineering European Union Event Fiber Fibrin Fibrinolysis Fibrinolytic Agents Fibroblasts Fibrosis Functional Imaging Future Goals Hematologist Hematology Hemorrhage Hemostatic function Hospitalization Human Human Engineering Hypertension Image Impairment In Situ In Vitro Infection Infiltration Injury Investigation Investments Label Leg Libraries Limb structure Lung Modeling Molecular Morbidity - disease rate Obstruction Pain Pathologic Pathology Patients Penetration Pericytes Pharmaceutical Preparations Pharmacotherapy Physician Executives Physiological Physiology Plasmin Plasminogen Postphlebitic Syndrome Process Proliferating Publications Pulmonary Embolism Pulmonary artery structure Reporting Resolution SARS-CoV-2 infection Scheme Services Site Smooth Muscle Myocytes Speed System Therapeutic Therapeutic Agents Thromboembolism Thrombolytic Therapy Thrombosis Thrombus Time Tissue Model Tissues Travel Ulcer United States Vascular Diseases Vasculitis Veins Venous Virus Diseases arm bioprinting coronavirus disease cost deep vein disability-adjusted life years drug candidate drug development drug testing experience high throughput screening improved in vitro Model miniaturize mortality next generation optoacoustic tomography pandemic preparedness photoacoustic imaging real-time images response screening small molecule thrombotic vascular injury venous thromboembolism years of life lost

项目摘要

Abstract Thrombosis, the obstruction of blood flow due to the formation of clot in blood vessels, accounts for 1 in 4 deaths worldwide. In particular, venous thrombi occur in deep veins most often in the legs or arms and is commonly known as deep vein thrombosis (DVT). DVT and pulmonary embolism are collectively referred to as venous thromboembolism (VTE) in which a part of the venous thrombus breaks off, travel to the lungs, and lodge in pulmonary arteries. VTE is the 3rd leading cause of cardiovascular-related deaths globally with estimates of >500,000 deaths in the United States every year. VTE is reported to be the leading cause of disability-adjusted life years lost in hospitalized patients. Despite the large amount of capital invested in drug development, very few drugs are ultimately proven useful in humans. Such a low yield occurs largely because planar cell culture and animal models for testing the drugs oftentimes fail to reflect human physiology/pathology. In contrast, three-dimensional (3D) human cell-based in vitro models have been increasingly adopted to improve drug testing by recapitulating physiological and pathological parameters of their human counterparts. In addition to the development of engineered human- based microtissues, real-time, in situ, non-invasive volumetric monitoring of the behaviors of the engineered vascular models and their responses towards viral infection/drug treatment is a key capacity to achieve high(er)-throughput and accurate in vitro screening of promising drug candidates. Here we propose to harness our unique expertise in engineered in vitro human vascular tissue models and high-speed label-free imaging of thrombosis with further aid by strong experiences in clinical hematology and anticoagulation management in patients. Together, we will create an enabling and first-of-its-kind high(er)- throughput real-time imaging-integrated thrombosis-on-chip model to study thrombosis and potential therapeutic agents, taking severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection as a timely example to instruct future preparedness for pandemics and other vascular disorders.

抽象的血栓形成，由于血管中凝块的形成引起的血流阻塞，四分之一占1 全球死亡。特别是，静脉血栓最常在腿或手臂上发生，是通常称为深静脉血栓形成（DVT）。 DVT和肺栓塞统称为静脉血栓栓塞（VTE），其中一部分静脉血栓破裂，前往肺部，然后肺动脉中的小屋。 VTE是全球心血管相关死亡的第三主要原因每年在美国估计> 500,000人死亡。据报道，VTE是住院的患者丧生的残疾调整后的生活年。尽管在药物开发上投资了大量资本，但最终很少有药物被证明有用在人类中。如此低的产量很大程度上是因为平面细胞培养和用于测试药物的动物模型通常无法反映人类的生理/病理学。相反，三维（3D）人类细胞基于通过概括生理学和其人类对应物的病理参数。除了开发设计的人类基于实时的实时微动物，对工程行为的行为的非侵入性体积监测血管模型及其对病毒感染/药物治疗的反应是实现的关键能力高（ER） - 直播和准确的有前途候选药物的体外筛查。在这里，我们建议利用我们在体外人体血管组织模型和在临床血液学和患者的抗凝治疗。我们将共同创建一个启示性和优先的高高（ER） - 吞吐量的实时成像集成在片上的集成性模型，以研究血栓形成和潜力治疗剂，服用严重的急性呼吸道综合征冠状病毒2（SARS-COV-2）感染及时指导未来的大流行病和其他血管疾病的准备。