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

肥厚性心脏病从分子途径到器官系统的系统生物学

• 批准号: 9302154
• 负责人: Andrew D. McCulloch
• 金额: $ 51.35万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-13 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9302154
• 关键词: 3-Dimensional; Affect; Agonist; Animal Model; Architecture; Biological Models; Biomechanics; Cardiac; Cardiac Myocytes; Cardiovascular system; Cells; Chronic; Clinical; Computer Simulation; Coupled; Data; Data Set; Development; Diffusion; Dimensions; Energy Metabolism Pathway; Extracellular Matrix; Failure; Fiber; Fibrosis; Gene Expression; Goals; Growth; Heart; Heart Diseases; Heart failure; Hereditary Disease; Hypertension; Hypertrophy; Image; In Vitro; Laws; Lead; Link; MAPK3 gene; Magnetic Resonance Imaging; Measurement; Measures; Mechanics; Mediating; Metabolic Pathway; Metabolism; Modeling; Molecular; Muscle Cells; Myocardial; Myocardium; Neonatal; Organ; Outcome; Pathogenesis; Pathway interactions; Patients; Physiologic intraventricular pressure; Play; Property; Proteomics; Public Health; Publishing; Rattus; Reproducibility; Research Personnel; Research Project Grants; Role; Sarcomeres; Series; Signal Pathway; Signal Transduction; Spatial Distribution; Stretch Receptors; Stretching; Systemic hypertension; Systems Biology; Testing; Time; Tissues; Ventricular; body system; c-myc Genes; diagnostic biomarker; disease natural history; experimental study; extracellular; genome-wide; hemodynamics; hypertensive heart disease; in vivo; innovation; mechanical force; molecular marker; mortality; multi-scale modeling; network models; novel; novel diagnostics; novel therapeutics; pressure; prevent; receptor; response; therapeutic target; tool; transcriptomics; ventricular hypertrophy

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.

抽象的 该提案将把心肌细胞肥大的新型细胞信号传导模型整合到器官水平连续体中 心室生长、重塑和机械能学模型与血流动力学模型相结合 全身性高血压。多尺度计算模型以及大鼠实验 心室血流动力学超负荷，将用于研究各向异性之间的相互作用 偏心心室肥厚发展中的牵张和神经激素信号传导途径， 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 压力超载的大鼠心脏以完善和验证肥厚调节的定量模型 网络。我们将使用主动脉带状和假手术的蛋白质组学和转录组学测量 大鼠心脏测试和完善各向异性拉伸和神经激素的定量系统模型 模拟体内心肌细胞肥大。我们还将对组织和器官规模进行建模和验证 由于心室压力超负荷导致心脏的生长和重塑。我们将结合心血管 全身血流动力学的系统模型到心室生长的三维连续模型 以及由肥大信号模型和细胞规模生长规律驱动的重塑。大规模数据集 根据大鼠的高场扩散张量磁共振成像和约束混合模型，添加 有关纤维结构和材料特性的详细信息。最后，我们将预测 心室肥厚的机械能后果。模型将扩展至包括改造 收缩力和能量代谢途径，并用于预测心肌的变化 压力过载期间的机械能学。然后，这些模型的预测将得到广泛的验证 体内力学（通过标记磁共振成像）和能量学的表征。这些新 模型将得到验证和优化，以帮助定义和分析相关的特定肥大途径 高血压患者的转化结果，最终有可能确定新的诊断方法 高血压心脏病的生物标志物和治疗靶点。