Multiscale modeling of inherited cardiomyopathies and therapeutic interventions

摘要 这项研究的目标是开发一个预测性的多尺度模型，以提高对家庭成员的理解 这可以用来帮助筛选潜在的心脏病新疗法。家族性 心肌病是最常见的遗传性心脏缺陷，影响着大约70万美国人。大部分 基因突变会影响肌球蛋白或调节肌球蛋白功能的调节蛋白。其中大部分都是 突变还会导致心脏异常生长，称为肥大。该项目将开发、校准和 验证一个创新的多尺度模型，该模型使用量化肌球蛋白水平函数的数据来预测心脏 随着时间的推移肥大。这是开发针对患者的计算机模型的关键一步，该模型可以 用于优化心力衰竭的治疗，并预测不同类型药物的效果 干预。在未来，人们可以想象临床医生在硅胶中测试药物治疗并选择 为患者带来最大长期利益的干预措施。 研究团队由两名生理学家/生物物理学家(Campbell和Yengo)和两名工程师(温克和 他们在心脏生物学方面有着共同的兴趣。总而言之，他们的研究技能涵盖了结构-功能 对肌球蛋白分子的分析，以计算机模拟随时间生长和重塑的心脏。这项研究 PLAN将最先进的分层耦合数学模型与验证实验相结合， 范围从停流分子动力学分析到心肌应变模式的磁共振成像。 该模型将使用从野生型小鼠和从 肌球蛋白调节光K104E突变导致心肌肥大的转基因动物 链条。其他测试将使用增强(奥米卡米夫)和抑制(Myk-461)的药物进行 肌球蛋白水平的收缩功能。 有三个具体目标。 目的1：将肌球蛋白的多态动力学模型集成到器官水平的有限框架中以预测 肌球蛋白功能的遗传和/或药物调节。 目标2：开发生长和重塑算法来预测心脏结构和功能的慢性变化 由于遗传和/或药物对肌球蛋白功能的调节。 目的3：利用量化不同空间和时间尺度的实验数据对模型进行校准和验证。

ABSTRACT The goal of this research is to develop a predictive multiscale model that will improve understanding of familial cardiomyopathies and that can be used to help screen potential new therapies for cardiac disease. Familial cardiomyopathies are the most frequently inherited heart defect and affect about 700,000 Americans. Most of the genetic mutations affect myosin or regulatory proteins that modulate myosin function. The majority of these mutations also induce abnormal cardiac growth termed hypertrophy. This project will develop, calibrate, and validate an innovative multiscale model that uses data quantifying myosin-level function to predict how hearts hypertrophy over time. This is a critical step on the path to developing patient-specific computer models that can be used to optimize treatments for heart failure and to predict the effects of different types of pharmaceutical intervention. In the future, one could envision clinicians testing drug treatments in silico and selecting the intervention that produces the greatest long-term benefit for their patient. The research team consists of two physiologists/biophysicists (Campbell & Yengo) and two engineers (Wenk & Lee) who share a common interest in cardiac biology. Together, their research skills span from structure-function analysis of myosin molecules to computer simulations of hearts that grow and remodel over time. The research plan integrates state-of-the-art hierarchically-coupled mathematical models with validation experiments that range from stopped-flow molecular kinetic assays to magnetic resonance imaging of myocardial strain patterns. The model will be tested using molecular to organ-level experimental data obtained from wild-type mice and from transgenic animals that develop cardiac hypertrophy because of a K104E mutation in myosin regulatory light chain. Additional tests will be performed using drugs that enhance (omecamtiv mecarbil) and inhibit (MYK-461) myosin-level contractile function. There are three specific aims. Aim 1: Integrate a multistate kinetic model of myosin into an organ-level finite framework to predict the effects of genetic and/or pharmaceutical modulation of myosin function. Aim 2: Develop growth and remodeling algorithms to predict chronic changes in ventricular structure and function resulting from genetic and/or pharmaceutical modulation of myosin function. Aim 3: Calibrate and validate the model using experimental data quantifying different spatial and temporal scales.