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

摘要 这一建议将把心肌细胞肥大的新细胞信号模型整合到器官水平的连续体中。 与血流动力学模型相耦合的心室生长、重塑和机械能模型 系统性高血压。大鼠多尺度计算模型及实验研究 对于心室血流动力学过载，将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偏心性心室肥厚发展中的作用 纤维化与高血压引起的心脏重构。具体地说，我们将使用来自 压力超负荷大鼠心脏肥厚调控量化模型的改进和验证 网络。我们将使用蛋白质组学和转录组学方法测量主动脉环扎组和假手术组 大鼠心脏测试和完善各向异性拉伸和神经激素的量化系统模型 体内模拟心肌细胞肥大。我们还将对组织和器官规模进行建模和验证 由于心脏压力超负荷而导致的心脏生长和重塑。我们将会把心血管疾病 从整体血流动力学的系统模型到心室生长的三维连续模型 肥大信号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-张量磁共振成像和受限的混合模型中，添加了 有关纤维结构和材料特性的详细信息。最后，我们将预测 心脏肥厚的机械能后果。模型将被扩展到包括改建 收缩能力和能量代谢途径，并用于预测心肌细胞的变化 压力超载过程中的机械能学。然后，这些模型预测将得到广泛的验证 活体力学(通过标记磁共振成像)和能量学的表征。这些新的 将对模型进行验证和优化，以帮助定义和分析相关的特定肥大途径 与高血压患者的转译结果有关，最终有可能识别新的诊断 高血压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.