3-Dimensional virtual ventricles to design precision therapies in hypertrophic cardiomyopathy

3 维虚拟心室设计肥厚型心肌病的精准疗法

• 批准号: 10381681
• 负责人: JONATHAN MORENO
• 金额: $ 14.3万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10381681
• 关键词: 3-Dimensional; Address; Adrenergic Agents; Adrenergic beta-Antagonists; Adult; Anti-Arrhythmia Agents; Architecture; Arrhythmia; Award; Biophysics; Calcium Channel Blockers; Cardiac; Cardiac Electrophysiologic Techniques; Cardiac Myocytes; Cardiology; Cardiomyopathies; Cardiovascular system; Cell Therapy; Cell model; Cells; Clinical; Clinical Data; Clinical Trials; Combination Drug Therapy; Combined Modality Therapy; Computer Models; Coupled; Data; Disease; Disopyramide; Doctor of Philosophy; Drug Combinations; Echocardiography; Electrophysiology (science); Failure; Fibrosis; Functional disorder; Genes; Genetic; Genotype; Geometry; Goals; Heart; Heart Abnormalities; Heart Diseases; Heart Transplantation; Heart failure; Human; Hypertrophic Cardiomyopathy; Image; Imaging Techniques; Inherited; Internal Medicine; Knowledge; Lead; Light; Link; Literature; Medical; Medical Genetics; Medicine; Mentorship; Microvascular Dysfunction; Modeling; Molecular; Multimodal Imaging; Muscle Cells; Mutation; National Heart, Lung, and Blood Institute; Obstruction; Optics; Organ; Pathologic; Pathway interactions; Patients; Pattern; Persons; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Precision therapeutics; Propranolol; Quality of life; Research; Research Personnel; Research Priority; Resources; Signal Pathway; Signal Transduction; Sodium; Specimen; Sudden Death; Symptoms; Testing; Therapeutic; Time; Tissues; Training; Ventricular; Ventricular Arrhythmia; Ventricular Remodeling; biophysical properties; cardiac magnetic resonance imaging; design; drug efficacy; drug testing; heart rhythm; high dimensionality; indium arsenide; insight; instructor; interdisciplinary approach; mortality; novel; novel therapeutics; optical imaging; patient response; preclinical study; predictive test; prevent; prospective; ranolazine; response; scaffold; skills; success; sudden cardiac death; targeted treatment; three-dimensional modeling; tool; virtual

Project Abstract Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease worldwide and is the leading cause of sudden cardiac death (SCD) in young people. Though HCM is characterized by more than 1400 mutations in the genes encoding the contractile apparatus of the cell, the pathophysiology of HCM encompasses diverse clinical symptoms; it can eventually lead to heart failure and fatal ventricular arrhythmia. Despite nearly 5 decades of research, there is currently no disease-modifying or mortality-reducing drug therapy for HCM patients. HCM treatment has failed for two key reasons: (1) arrhythmias are an emergent phenomena in space and time: single cell markers of arrhythmia fail to predict the effects on the whole heart; and (2) HCM is markedly heterogeneous - it is likely there are specific molecular underpinnings leading to differential drug efficacy that are not appreciated in large clinical trials and preclude a “one-size-fits-all” approach. I hypothesize that the key to understanding the therapeutic potential of drug therapy for HCM is through patient-specific modeling of their cardiac electrophysiology and ventricular ultrastructure. Thus, the goal of this research award is to merge clinical data, genetics, advanced imaging, and biophysical characterization of HCM to understand how higher dimensional ultrastructural remodeling influences cellular electrophysiology to design precision-targeted drug therapy. Specifically, I will develop a detailed electrophysiologic model of HCM that recapitulates mutation-specific alterations to better understand key determinants of success and failure for drug therapy. I will study patient-specific responses to two test drugs: ranolazine and b-blockers by optical imaging of dissociated adult cardiomyocytes of patients with HCM. I will then use multimodal imaging to characterize ventricular geometry and myofiber architecture of these patients to create a 3D virtual ventricle to test our single cell drug predictions. These aims will allow us me understand the bidirectional relationship between ventricular remodeling and single cell electrophysiology and drug therapy. I believe I have the appropriate background and resources to address the knowledge gaps described but require additional mentorship and training to transition to independence. I previously earned a PhD in computational cardiology and have undertaken additional training in basic and translational cardiovascular research. I have completed clinical training in Internal Medicine, Cardiology, Echocardiography, and Advanced Heart Failure and Cardiac Transplant, and have been appointed Instructor of Medicine as of July 1, 2020. To transition to an independent investigator, this K08 award will allow me to focus on developing new experimental skillsets in cellular electrophysiology, optical imaging techniques, as well as cardiac MRI and echo imaging that will compliment his computational background. At the conclusion of this award period, I will have acquired the skills to become a leader in translational characterization of heart failure and cardiomyopathies with the ultimate goal of designing novel therapies for patients suffering from these diseases.

项目摘要 肥厚型心肌病(HCM)是全世界最常见的遗传性心脏病，是 年轻人心源性猝死(SCD)的主要原因。尽管HCM的特点是有1400多个 编码细胞收缩装置的基因突变，肥厚性心肌病的病理生理学包括 多种临床症状；它最终可导致心力衰竭和致命性室性心律失常。尽管几乎 经过50年的研究，目前还没有针对肥厚型心肌炎的疾病修正或降低死亡率的药物疗法 病人。HCM治疗失败有两个关键原因：(1)心律失常是太空中的一种紧急现象 和时间：心律失常的单细胞标记物不能预测对整个心脏的影响；以及(2)HCM显著 异质性-很可能有特定的分子基础导致不同的药物疗效 在大型临床试验中得不到重视，并排除了“一刀切”的方法。 我推测，理解药物治疗对肥厚型心肌炎治疗潜力的关键是通过 他们的心脏电生理学和心脏超微结构的特定患者建模。因此，这一目标是 研究奖是将临床数据、遗传学、先进成像和生物物理特征结合在一起 了解高维超微结构重塑如何影响细胞 电生理学以设计精确的靶向药物疗法。具体地说，我将制定一个详细的 重述突变特异性改变以更好地理解关键的肥厚性心肌病电生理模型 药物治疗成败的决定因素。我将研究患者对两种测试药物的具体反应： 雷诺嗪和b-受体阻滞剂对肥厚性心肌病患者分离的成年心肌细胞的光学成像。这就做 然后使用多模式成像来表征这些患者的脑室几何结构和肌纤维结构 创建一个3D虚拟脑室来测试我们的单细胞药物预测。这些目标将使我们了解 单细胞电生理和药物治疗与心室重构的双向关系。 我相信我有适当的背景和资源来解决所描述的知识差距，但 需要额外的指导和培训才能过渡到独立。我之前获得了博士学位。 计算心脏病学，并接受了基础和转化性心血管方面的额外培训 研究。我已经完成了内科、心脏病学、超声心动图和高级临床培训 心力衰竭和心脏移植，自2020年7月1日起被任命为医学讲师。至 过渡到一名独立的研究员，这个K08奖将让我专注于开发新的实验 掌握细胞电生理学、光学成像技术以及心脏MRI和ECHO方面的技能 这将是对他的计算背景的补充。在颁奖期结束时，我将 已经获得了成为心力衰竭和心肌病翻译特征方面的领导者的技能 最终目标是为患有这些疾病的患者设计新的治疗方法。