Multiscale Modeling of Right Ventricular Fibrotic Remodeling in Pulmonary Arterial Hypertension

肺动脉高压右心室纤维化重塑的多尺度建模

• 批准号: 10337231
• 负责人: Daniela Valdez-Jasso
• 金额: $ 38.17万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10337231
• 关键词: Animal Model; Automobile Driving; Biological; Biomechanics; Blood Vessels; Cardiac; Chronic; Clinical Research; Collagen; Core-Binding Factor; Data; Differential Equation; Dilatation - action; Disease; Disease Progression; Extracellular Matrix; Fibroblasts; Fibrosis; Geometry; Goals; Hospitalization; Hypertrophy; Impairment; In Vitro; Lung; Measurement; Measures; Mechanics; Mediating; Modeling; Morbidity - disease rate; Muscle Cells; Myocardial; Myocardium; Outcome; Pathogenesis; Pathway interactions; Patient Rights; Patients; Phase; Phenotype; Physiological; Physiology; Profibrotic signal; Prognosis; Property; Property Rights; Rattus; Regulation; Research; Right Ventricular Dysfunction; Right Ventricular Function; Right ventricular strain; Sampling; Signal Pathway; Signal Transduction; Stimulus; Stress; Structure; Systems Biology; Testing; Time; Tissues; United States; Vascular Diseases; Ventricular; biomechanical test; design; electric impedance; experimental study; hemodynamics; in vitro Model; in vivo; mathematical model; mechanical load; mechanical properties; mortality; multi-scale modeling; network models; new therapeutic target; novel; patient prognosis; preservation; prevent; pulmonary arterial hypertension; pulmonary arterial pressure; recruit; response; right ventricular failure; right ventricular remodeling

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.

项目总结 肺动脉高压(PAH)是一种肺血管疾病。 重塑，在这种情况下，患者死亡率与右室功能受损显著相关。这个 PAH患者预后很差，5年存活率为50%，无1例死亡。 预防PAH右心衰竭的有效治疗方法。申请者所在小组最近的研究 在PAH的动物模型和临床研究中已经表明，改变的右室舒张期僵硬是 PAH发病机制的一个重要特征。在这里，我们建议调查结构 右室细胞外基质重塑改变其力学性能的机制 房车机械载荷和材料变化的特性和细胞机制 属性反过来调节心脏成纤维细胞的表型和促纤维化信号。使用 在已建立的多环芳烃进展的动物模型中，我们将 进行详细的活体生理研究和双轴组织生物力学测试 和脱细胞房车样本一起结合微观结构数学模型来确定 ECM重塑如何改变右室心肌力学和舒张期功能。到时候我们会的 在一种新的体外模型中总结这些RV ECM结构和力学的变化 PAH中ECM结构和负荷状态的改变对RV心脏的调节作用 成纤维细胞(CFB)的分化、激活和促纤维化的ECM表达。最后，我们将使用 这些新的体外测量扩展和验证了一个力学模型。 调节CBF细胞信号。这项提案的具体目标将决定时间进程 RV几何形状、收缩性能和舒张期材料特性的变化 在PAH期间改变血流动力学负荷，并确定这些机制是如何 适应不良(目标1)；适应和恢复过程中右室心肌结构和力学的变化。 适应性不良的RV ECM重构，并确定驱动这些变化的生物力学刺激因素 在PAH中(目标2)；以及调节适应性和非适应性RV的机械生物学机制 PAH期间ECM重塑(AIM 3)。拟议研究的总体结果将是 RV细胞外基质(ECM)重塑的定量生物学原理的发现 在PAH进展过程中所发生的舒张期功能的改变和 过渡到失代偿性房室功能障碍。