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.

项目概要 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 的外在和内在心脏影响。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， SARS-CoV-2 冠状病毒引起的临床疾病，最近变得越来越明显： 其他器官系统也参与其中，包括心脏和血液。例如，心律失常是严重的 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 环境中已有的心血管疾病。最近的两份报告表明，20-22% SARS-Cov-2 住院患者出现心脏损伤，这些患者的心脏损伤率高达 50% 死亡率比没有心脏损伤的患者高出一个数量级以上。心脏 心律失常或心肌损伤严重危及生命，可由多种因素引起，包括 疾病（例如高血压）、药物，还有病毒感染和全身炎症。另外，一个州 过度凝血也被描述为 COVID-19 的一个核心特征，导致血液凝块， 肺栓塞和右心衰竭会危及生命。该项目的具体目标是： 1) 评估 DS-iKL 作为减轻 SARS-CoV-2 引发的心脏影响的新型疗法的潜力 使用 iPS 的多器官微生理系统进行细胞因子风暴（凝血和血管通透性） 衍生的人心肌细胞和血管内皮； 2) 评估Notch信号的潜力 抑制剂 DAPT 对器官型组织中的病毒感染性以及 SARS-CoV-2 的内在心脏影响 健康和易患成人心脏组织的切片模型。我们预计会产生丰富的数据集 从这些实验中可以看出 DS-iKL 和 DAPT 在减轻 SARS-CoV-2 的外在和内在心脏影响。该研究计划还将产生一条体内途径 人类研究加速翻译。最后，DS-iKL 和 DAPT 对缓解 SARS-CoV-2 的影响可能也适用于其他具有共同特征的炎症和传染病 相似的疾病病因。