Systems Biology of Hypertrophic Heart Disease from Molecular Pathways to Organ System

摘要 这一建议将整合新的细胞信号模型的心肌细胞肥大到器官水平的连续 心室生长、重塑和机械能模型与 全身性高血压多尺度计算模型，以及大鼠实验， 心室血流动力学过载，将被用来研究各向异性之间的相互作用 牵张和神经激素信号通路在离心性心室肥大的发展中， 纤维化和高血压引起的心脏重塑。具体来说，我们将使用来自 压力超载大鼠心脏，以完善和验证肥大调节的定量模型 网络.我们将使用蛋白质组学和转录组学的测量， 大鼠心脏测试和完善定量系统模型的各向异性拉伸-和神经- 模拟体内心肌细胞肥大。我们还将模拟和验证组织和器官规模 由于心室压力超负荷导致的心脏生长和重塑。我们将心血管 从全身血液动力学系统模型到心室生长的三维连续模型 以及由肥大信号传导模型和细胞尺度生长规律驱动的重塑。大规模数据集 从大鼠的高场扩散张量磁共振成像和约束混合模型中，添加 纤维结构和材料特性的详细信息。最后，我们将预测 心室肥大的机械能后果。模型将扩展到包括改造 收缩力和能量代谢途径，并用于预测心肌细胞的变化， 压力过载时的机械能学。这些模型预测将得到广泛的验证 体内力学（通过标记的磁共振成像）和能量学的表征。这些新 模型将被验证和优化，以帮助定义和分析特定的肥大途径相关 高血压患者的转化结果，最终有可能确定新的诊断方法， 高血压性心脏病的生物标志物和治疗靶点。

Abstract This proposal will integrate novel cell signaling models of myocyte hypertrophy into organ-level continuum models of ventricular growth, remodeling and mechanoenergetics coupled to hemodynamic models of systemic hypertension. The multi-scale computational models, together with experiments in rats subjected to ventricular hemodynamic overload, will be used to investigate the interactions between anisotropic stretch and neurohormonal signaling pathways in the development of eccentric ventricular hypertrophy, fibrosis and hypertension-induced cardiac remodeling. Specifically, we will use genome-scale data from pressure-overloaded rat hearts to refine and validate quantitative models of hypertrophic regulatory networks. We will use proteomic and transcriptomic measurements from aortic-banded and sham-operated rat hearts to test and refine quantitative systems models of anisotropic stretch- and neurohormonally- simulated cardiac myocyte hypertrophy in vivo. We will also model and validate tissue- and organ-scale growth and remodeling of the heart due to ventricular pressure overload. We will couple cardiovascular system-models of whole body hemodynamics to three-dimensional continuum models of ventricular growth and remodeling driven by hypertrophic signaling models and cell-scale growth laws. Large-scale data sets from high-field diffusion-tensor magnet resonance imaging in the rat, and constrained mixture models, add detailed information on fiber architecture and material properties. Finally, we will predict mechanoenergetic consequences of ventricular hypertrophy. Models will be extended to include remodeling of contractility and energy metabolism pathways, and used to predict alterations in myocardial mechanoenergetics during pressure overload. These model predictions will then be validated with extensive characterization of in-vivo mechanics (by tagged magnetic resonance imaging) and energetics. These new models will be validated and optimized to help define and analyze specific hypertrophic pathways relevant to translational outcomes in hypertensive patients, with the ultimate potential of identifying new diagnostic biomarkers and therapeutic targets for hypertensive heart disease.