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

• 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
• 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

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.

摘要 血栓形成是由于血管内凝块形成而导致的血液流动障碍，占四分之一。 世界各地的死亡人数。特别是，静脉血栓最常发生在腿部或手臂的深静脉，而且是 通常被称为深静脉血栓形成(DVT)。深静脉血栓和肺栓塞统称为 静脉血栓栓塞症(VTE)，部分静脉血栓破裂，进入肺部， 住在肺动脉里。VTE是全球心血管相关死亡的第三大原因， 据估计，美国每年有50万人死亡。据报道，VTE是导致 住院患者的伤残调整寿命年损失。 尽管在药物开发上投入了大量资本，但最终被证明有效的药物很少。 在人类身上。如此低的产量在很大程度上是因为平面细胞培养和测试药物的动物模型 通常不能反映人类的生理/病理。相比之下，基于三维(3D)的人体细胞 体外模型已越来越多地被采用来改进药物测试，通过概括生理和 人类同类的病理参数。除了基因工程人类的发展之外- 基于显微组织的，实时、原位、非侵入性的工程化行为的体积监测 血管模型及其对病毒感染/药物治疗的反应是实现 高通量和准确的潜在候选药物的体外筛选。 在这里，我们建议利用我们在体外工程人类血管组织模型和 在血液学和血液学方面的丰富经验的进一步帮助下，对血栓形成的高速无标记成像 患者的抗凝治疗。我们将共同打造一个赋能的、首创的高(呃)- 通过实时成像集成的芯片血栓形成模型来研究血栓形成和潜力 以严重急性呼吸综合征冠状病毒2型感染为基础的治疗药物 及时树立榜样，指导今后为大流行和其他血管疾病做好准备。