A 3D IN VITRO DISEASE MODEL OF ATRIAL CONDUCTION

心房传导 3D 体外疾病模型

• 批准号: 10166441
• 负责人: David Terry Curiel
• 金额: $ 72.36万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10166441
• 关键词: 2019-nCoV; 3-Dimensional; Acute; Address; Adult; Adult Respiratory Distress Syndrome; Arrhythmia; Blood; Blood coagulation; COVID-19; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Cells; Cessation of life; Clinical; Coagulation Process; Collaborations; Communicable Diseases; Coronavirus; Data Set; Deep Vein Thrombosis; Diamond; Disease; Disease model; Embolism; Endothelial Cells; Endothelium; Etiology; Goals; Heart; Heart Atrium; Heart Injuries; Heart failure; Human; Hypertension; In Vitro; Individual; Infection; Inflammation; Inflammatory; Integration Host Factors; Laboratories; Leukocytes; Life; Lung; Mediator of activation protein; Methodology; Microfluidics; Modeling; Morbidity - disease rate; Muscle Cells; Myocardial; Myocardial Infarction; Myocarditis; Myocardium; Patients; Pharmaceutical Preparations; Positioning Attribute; Proteoglycan; Publishing; Reporting; Research; Severe Acute Respiratory Syndrome; Side; Signal Transduction; Slice; Source; Supporting Cell; Testing; Therapeutic; Tissues; Translations; Transplantation; Universities; Vascular Endothelium; Vascular Permeabilities; Viral; Virus; Virus Diseases; Washington; base; biosafety level 3 facility; body system; comorbidity; coronavirus disease; cytokine; cytokine release syndrome; experience; experimental study; in vivo; in vivo Model; induced pluripotent stem cell; inhibitor/antagonist; injured; innovation; microphysiology system; mortality; myocardial injury; notch protein; novel; novel therapeutics; organ on a chip; response; sudden cardiac death; therapeutic target; trafficking

PROJECT SUMMARY The primary goal of this one-year competitive revision is to assess the potential of two novel therapeutics (DS-iKL and DAPT) to mitigate the extrinsic and intrinsic cardiac effects of SARS-CoV-2, respectively. This is important because, while acute respiratory distress is a major cause of morbidity and mortality of COVID-19, the clinical disease caused by the SARS-CoV-2 coronavirus, it has more recently become widely evident that other organ systems are involved including the heart and blood. For example, cardiac arrhythmias are a major source of morbidity and mortality (44-60%) associated with COVID-19 disease, especially in individuals with pre-existing cardiovascular disease in ICU settings. Two recent reports have indicated that 20-22% of hospitalized patients with SARS-Cov-2 experience cardiac injury, and these patients suffer a staggering 50% mortality rate, more than an order of magnitude greater than those patients without cardiac injury. Cardiac arrythmias or myocardial injury are acutely life threatening and can be caused by a host of factors including co- morbidities (e.g., hypertension), drugs, but also viral infection and systemic inflammation. In addition, a state of hyper coagulation has also been described as a central feature of COVID-19, leading to blood clots that can be life threatening as pulmonary emboli and right-sided cardiac failure. The specific aims of the project are to: 1) Assess the potential of DS-iKL as a novel therapeutic to mitigate the cardiac effects of SARS-CoV-2 initiated cytokine storm (coagulation and vascular permeability) using a multi-organ microphysiological system of iPS- derived human cardiomyocytes and vascular endothelium; 2) Assess the potential of the Notch signaling inhibitor, DAPT, on viral infectivity and thus intrinsic cardiac effects of SARS-CoV-2, in an organotypic tissue slice model of healthy and predisposed adult human cardiac tissue. We anticipate a rich data set resulting from these experiments that should demonstrate the exciting potential of DS-iKL and DAPT to mitigate the extrinsic and intrinsic cardiac effects of SARS-CoV-2. The research plan will also produce a path to in vivo human studies to accelerate translation. Finally, the potential impact of DS-iKL and DAPT to mitigate the effects of SARS-CoV-2 are likely to also be applicable to other inflammatory and infectious diseases that share similar disease etiology.

项目摘要 这项为期一年的竞争性修订的主要目标是评估两种新疗法的潜力 （DS-iKL和DAPT）分别减轻SARS-CoV-2的外在和内在心脏效应。这是 重要的是，虽然急性呼吸窘迫是COVID-19发病和死亡的主要原因， 由SARS-CoV-2冠状病毒引起的临床疾病，最近已经广泛证明， 包括心脏和血液在内的其他器官系统也受到影响。例如，心律失常是一种主要的 与COVID-19疾病相关的发病率和死亡率（44-60%）的来源，特别是在患有 ICU环境中的既存心血管疾病。最近的两份报告表明， 患有SARS-Cov-2的住院患者经历了心脏损伤，这些患者遭受了惊人的50% 死亡率比没有心脏损伤的患者高出一个数量级。心脏 心律失常或心肌损伤是急性危及生命的，并且可以由许多因素引起， 病态（例如，高血压）、药物，而且还有病毒感染和全身性炎症。此外，一个国家 高凝状态也被描述为COVID-19的中心特征，导致血液凝块， 可能危及生命，如肺栓塞和右侧心力衰竭。该项目的具体目标是： 1)评估DS-iKL作为一种新型治疗药物缓解SARS-CoV-2启动的心脏效应的潜力 细胞因子风暴（凝血和血管通透性），使用iPS的多器官微生理学系统， 来源于人心肌细胞和血管内皮细胞; 2）评估Notch信号传导的潜力， 抑制剂DAPT在器官型组织中对病毒感染性和SARS-CoV-2内在心脏效应的影响 健康和易感成人心脏组织切片模型。我们预计会产生丰富的数据集， 从这些实验中，应该证明DS-iKL和DAPT的激动人心的潜力， SARS-CoV-2的外在和内在心脏效应。该研究计划还将产生一种途径， 人类研究加速翻译。最后，DS-iKL和DAPT缓解 SARS-CoV-2的影响可能也适用于其他炎症和感染性疾病， 类似的疾病病因。