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

基本信息

批准号：
10215670
负责人：
JONATHAN MORENO
金额：
$ 14.3万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10215670
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 Magnetic Resonance Imaging 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 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 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

项目摘要

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）是世界范围内最常见的遗传性心脏病，也是最常见的遗传性心脏病。尽管 HCM 的特征有 1400 多种，但它是年轻人心源性猝死 (SCD) 的主要原因。编码细胞收缩装置的基因发生突变，HCM 的病理生理学包括不同的临床症状；尽管几乎可以导致心力衰竭和致命的室性心律失常。经过 5 年的研究，目前还没有针对 HCM 的疾病缓解或降低死亡率的药物疗法 HCM 治疗失败的主要原因有两个：（1）心律失常是太空中的一种新兴现象。和时间：心律失常的单细胞标记物无法预测对整个心脏的影响；(2) HCM 明显；异质性 - 可能存在特定的分子基础导致不同的药物功效在大型临床试验中不受重视，并且排除了“一刀切”的方法。我认为了解 HCM 药物治疗潜力的关键是通过患者特定的心脏电生理学和心室超微结构建模因此，这是本研究的目标。研究奖旨在融合临床数据、遗传学、先进成像和生物物理特征 HCM 了解高维超微结构重塑如何影响细胞具体来说，我将制定详细的电生理学来设计精准靶向药物治疗。 HCM 电生理模型概括了突变特异性改变，以更好地理解关键我将研究患者对两种测试药物的特定反应：我将通过光学成像对 HCM 患者的分离的成年心肌细胞进行雷诺嗪和 b 受体阻滞剂的研究。然后使用多模态成像来表征这些患者的心室几何形状和肌纤维结构创建 3D 虚拟心室来测试我们的单细胞药物预测。这些目标将使我们能够了解心室重塑与单细胞电生理学和药物治疗之间的双向关系。我相信我有适当的背景和资源来解决所描述的知识差距，但是我之前获得了博士学位，需要额外的指导和培训才能过渡到独立。计算心脏病学，并接受了基础和转化心血管方面的额外培训我已完成内科、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，并自 2020 年 7 月 1 日起被任命为医学讲师。过渡到独立研究者，这个 K08 奖项将使我能够专注于开发新的实验细胞电生理学、光学成像技术以及心脏 MRI 和回波方面的技能图像将补充他的计算背景在这个奖项期结束时，我将已获得成为心力衰竭和心肌病转化表征领域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疗法。