Multi-scale Systems Model of Murine Heart Failure

描述（由申请人提供）：心力衰竭是一个快速增长的健康问题，导致心律失常或泵衰竭死亡。心肌细胞神经体液调节、离子电流、钙（Ca 2+）处理和收缩力的改变，伴随心室肥大和结构重塑，都有助于心力衰竭。了解这些复杂的生物化学和生物物理功能的相互作用，需要定量系统模型，也集成了多个物理尺度。为了验证计算模型，需要具有良好特性和易于扰动的实验系统。现在有许多基因靶向小鼠模型，概括了心力衰竭的主要病理生理学和临床特征。在小鼠中可以测量的信号传导，电生理学，Ca 2+处理，肌丝功能和组织结构的变化的多尺度数据的财富不能在人类中获得，但这里提出的新模型将提供一个系统的框架，以将发现外推到临床环境。Ca 2 +-钙调蛋白依赖性蛋白激酶（CaMKII）在心力衰竭中上调且更活跃，并且是促成心力衰竭中的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剂。CaMKII过表达导致小鼠心力衰竭，而CaMKII敲除或抑制可以防止心力衰竭。虽然其他途径也很重要，但我们在这里集中于小鼠模型，其中多种关键心力衰竭表型都受到CaMKII无效或过度表达的影响。我们将利用我们实验室正在进行的研究来扩展模型制定和验证所需的丰富实验数据集。 研究人员提出了一种新颖的实验和计算研究的紧密结合，利用PI（UCD的Bers和UCSD的McCulloch）与戴维斯（Colleen Clancy和Leighton伊豆），圣地亚哥（Joan Heller Brown和Jeffrey Omens）和弗吉尼亚大学（Jeffrey Saucerman）的合作教师之间强大的跨学科协同作用。本研究旨在验证我们的总体假设，即Ca ~（2+）-CaMK Ⅱ信号通路控制着多个多尺度过程，这些过程在适应不良的电生理、Ca ~（2+）处理、收缩和肥厚性重构中协同作用，导致心力衰竭，包括：（1）2-肾上腺素能受体与CaMK Ⅱ信号通路之间的串扰;（3）细胞、组织和器官尺度的心脏机械功能障碍;和（4）响应于应激的肥大转录和适应不良的重构。每个目标包括新模型的制定和敏感性分析，利用基因工程小鼠的验证研究，以及特定假设的测试。模型和数据将利用加州大学圣地亚哥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存储库，并通过加州大学戴维斯分校开发的LabHeart软件工具的新版本免费广泛分发。 心力衰竭是一个日益严重的公共卫生问题，影响超过500万美国人，五年生存率很低。它是一种复杂的综合征，影响心脏的激素，电和机械功能。该建议使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，将衰竭心脏的各种改变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.