Multi-scale Systems Model of Murine Heart Failure

描述(申请人提供)：心力衰竭是一种快速增长的健康问题，会导致心律失常或泵衰竭而死亡。心肌细胞神经体液调节、离子电流、钙(Ca~(2+))处理和收缩能力的改变，伴随着心室肥厚和结构重塑，都是导致心力衰竭的原因。要了解这些复杂的生化和生物物理功能之间的相互作用，需要多个物理尺度上集成的定量系统模型。为了验证计算模型，需要具有良好特性且容易受到干扰的实验系统。现在有许多基因靶向的小鼠模型，概括了心力衰竭的主要病理生理和临床特征。可以在小鼠身上测量的信号、电生理学、钙处理、肌丝功能和组织结构变化的丰富的多尺度数据无法在人类身上获得，但这里提出的新模型将提供一个系统框架，将结果推断到临床环境中。钙调素依赖的蛋白激酶(CaMKII)在心力衰竭中表达上调且更为活跃，是心力衰竭时急性机械和电功能障碍以及慢性心脏重塑的细胞子系统的关键调节因子。CaMKII过表达导致小鼠心力衰竭，而CaMKII基因敲除或抑制可以保护小鼠免受心力衰竭的影响。虽然其他途径也很重要，但我们在这里重点关注的是多种关键心力衰竭表型都受到CaMKII表达缺失或过度表达影响的小鼠模型。我们将利用我们实验室中正在进行的研究来扩展模型制定和验证所需的丰富的实验数据集。研究人员建议将新颖的实验和计算研究紧密结合起来，利用PI(UCD的BERS和UCSD的McCulloch)与Davis(Colleen Clancy和Leighton Izu)、圣地亚哥(Joan Heller Brown和Jeffrey Omens)和弗吉尼亚大学(Jeffrey Saucerman)的协作教师之间强大的跨学科协同效应。这些目标检验了我们的总体假设，即钙-CaMKII信号控制着多个多尺度的过程，这些过程在导致心力衰竭的适应不良电生理、钙处理、收缩和肥大重建中协同作用，包括：(1)2-肾上腺素能受体和CaMKII信号之间的串扰；(2)在亚细胞、细胞、组织和器官水平触发心律失常易感性；(3)细胞、组织和器官水平的心脏机械功能障碍；以及(4)应激反应的肥大转录和适应不良重建。每个目标包括新模型的制定和敏感性分析，利用基因工程小鼠进行的验证研究，以及特定假说的测试。模型和数据将利用加州大学圣迭戈分校国家生物医学计算资源支持的软件和数据库基础设施，通过CellML储存库，以及加州大学戴维斯分校开发的新版本的LabHeart软件工具，自由和广泛地分发。 与公共健康相关：心力衰竭是一个日益严重的公共健康问题，影响着500多万美国人，五年存活率很低。这是一种复杂的综合征，会影响心脏的激素、电和机械功能。这项建议利用系统生物学的工具，特别是计算机模型和基因工程模型生物，将衰竭心脏的各种变化的信息合成到一个集成的计算机模型中，以更好地理解和治疗心力衰竭。

DESCRIPTION (provided by applicant): Heart failure is a rapidly growing health problem, leading to death from arrhythmias or pump failure. Alterations in myocyte neurohumoral regulation, ion currents, calcium (Ca2+) handling, and contractility, accompanied by ventricular hypertrophy and structural remodeling all contribute to heart failure. Understanding the interactions of these complex biochemical and biophysical functions requires quantitative systems models that also integrate over multiple physical scales. Well-characterized and readily perturbed experimental systems are needed to validate computational models. There are now many gene-targeted mouse models that recapitulate major pathophysiological and clinical features of heart failure. The wealth of multi-scale data on alterations in signaling, electrophysiology, Ca2+ handling, myofilament function and tissue structure that can be measured in mice cannot be obtained in humans, but the new models proposed here will provide a systematic framework to extrapolate findings to the clinical setting. Ca2+-calmodulin dependent protein kinase (CaMKII) is upregulated and more active in heart failure, and is a key regulator of cellular subsystems contributing to acute mechanical and electrical dysfunction as well as chronic cardiac remodeling in heart failure. CaMKII overexpression leads to heart failure in mice, while CaMKII knockout or inhibition can protect against failure. While other pathways are also important, we focus here on mouse models in which multiple key heart failure phenotypes are all affected by null- or over-expression of CaMKII. We will take advantage of ongoing studies in our labs to extend the rich set of experimental data required for model formulation and validation. The investigators propose a closely integrated combination of novel experimental and computational studies that take advantage of strong interdisciplinary synergy between the PIs (Bers at UCD & McCulloch at UCSD) and collaborating faculty at Davis (Colleen Clancy and Leighton Izu), San Diego (Joan Heller Brown and Jeffrey Omens) and the University of Virginia (Jeffrey Saucerman). The aims test our overall hypothesis that Ca2+-CaMKII signaling controls multiple multi-scale processes that synergize in maladaptive electrophysiological, Ca2+ handling, contractile and hypertrophic remodeling leading to heart failure, including: (1) crosstalk between 2-adrenergic receptor and CaMKII signaling; (2) triggered arrhythmia susceptibility at the subcellular, cellular, tissue and organ scales; (3) cardiac mechanical dysfunction at cell, tissue and organ scales; and (4) hypertrophic transcription and maladaptive remodeling in response to stress. Each aim includes the formulation and sensitivity analysis of new models, validation studies making use of genetically engineered mice, and testing of specific hypotheses. Models and data will be distributed freely and widely making use of software and database infrastructure supported by the National Biomedical Computation Resource at UCSD, via the CellML repository, and through new releases of LabHeart software tool developed by the UC Davis group. PUBLIC HEALTH RELEVANCE: Heart failure is a growing public health problem that affects over 5 million Americans and has poor five-year survival. It is a complex syndrome that affects the hormonal, electrical and mechanical functions of the heart. This proposal uses the tools of systems biology, especially computer models and genetically engineered model organisms, to synthesize information on the diverse alterations in the failing heart into an integrated computer model for better understanding and treatment heart failure.