Multiscale Modeling of Right Ventricular Fibrotic Remodeling in Pulmonary Arterial Hypertension

项目摘要 肺动脉高压（PAH）是一种肺动脉血管疾病， 重构，其中患者死亡率与RV功能受损显著相关。的 PAH患者的预后非常差，5年生存率<50%， 预防PAH患者右心衰竭的现有疗法。申请人小组最近的研究 在PAH动物模型和临床研究中，已经表明改变的RV舒张刚度是 PAH发病机制的一个重要特征。在这里，我们建议调查的结构 RV细胞外基质（ECM）重塑改变其机械性能的机制 RV机械负荷和材料变化的性质和细胞机制 这些特性反过来调节心脏成纤维细胞的表型和促纤维化信号传导。使用 在一个完善的PAH进展动物模型中进行全面的时间过程，我们将 进行详细的体内生理研究和双轴组织生物力学测试， 和脱细胞RV样品以及微结构数学建模，以确定 ECM重塑如何改变RV心肌力学和舒张功能。然后我们将 在一种新的体外模型中概括了RV ECM结构和力学的这些变化， 探讨PAH中改变的ECM结构和负载条件如何调节RV心脏 成纤维细胞（CFB）分化、活化和促纤维化ECM表达。最后，我们将使用 这些新的体外测量扩展和验证机械的数学模型， 调节CBF细胞信号传导。这项建议的具体目标将决定时间进程 RV几何结构、收缩性和舒张材料特性的变化， PAH期间改变血流动力学负荷，并确定这些机制如何成为 适应不良（目的1）;适应和 适应不良的RV ECM重塑，并确定驱动这些变化的生物力学刺激 PAH（目的2）;以及调节适应性和适应不良RV的机械生物学机制 PAH期间ECM重塑（目的3）。拟议研究的总体成果将是 发现RV细胞外基质（ECM）重塑的定量生物学原理， 有助于PAH进展期间发生的舒张功能变化， 转变为失代偿性右心室功能障碍。

PROJECT SUMMARY Pulmonary arterial hypertension (PAH) is a disease of the pulmonary arterial vasculature and its remodeling, in which patient mortality is significantly associated with impaired RV function. The prognosis of patients with PAH is very poor with five-year survival <50%, and there are no available therapies to prevent right heart failure in PAH. Recent studies by the applicant’s group in animal models of PAH and clinical studies have shown that altered RV diastolic stiffness to be an important feature of PAH pathogenesis. Here we propose to investigate the structural mechanisms by which remodeling of RV extracellular matrix (ECM) alters their mechanical properties and the cellular mechanisms by which changes in RV mechanical loading and material properties in turn regulate the phenotype and pro-fibrotic signaling of cardiac fibroblasts. Using a comprehensive time-course in a well-established animal model of PAH progression, we will conduct detailed in-vivo physiological studies and biaxial tissue biomechanical testing of intact and decellularized RV samples together with microstructural mathematical modeling to determine how ECM remodeling alters RV myocardial mechanic and diastolic function. We will then recapitulate these alterations in RV ECM structure and mechanics in a novel in-vitro model to investigate how altered ECM structure and loading conditions in PAH regulate RV cardiac fibroblasts (CFB) differentiation, activation, and pro-fibrotic ECM expression. Finally, we will use these new in-vitro measurements to extend and validate a mathematical model of mechano- regulated CBF cell signaling. The specific aims of this proposal will determine the time course of changes in RV geometry, contractility and diastolic material properties that compensate for altered hemodynamic loads during PAH and determine how these mechanisms become maladaptive (Aim 1); the changes in RV myocardial structure and mechanics during adaptive and maladaptive RV ECM remodeling, and identify the biomechanical stimuli driving these changes in PAH (Aim 2); and the mechanobiological mechanisms regulating adaptive and maladaptive RV ECM remodeling during PAH (Aim 3). The overall outcome of the proposed research will be the discovery of quantitative biological principles of the RV extracellular matrix (ECM) remodeling that contribute to the changes in diastolic function that occur during the progression of PAH and the transition to decompensated RV dysfunction.