Multi-scale Systems Model of Murine Heart Failure

小鼠心力衰竭的多尺度系统模型

• 批准号: 8625824
• 负责人: Donald M Bers
• 金额: $ 69.57万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8625824
• 关键词: Acute; Adrenergic Receptor; Affect; American; Animal Model; Arrhythmia; Biochemical; Biological Models; Biomedical Computing; Ca(2+)-Calmodulin Dependent Protein Kinase; Calcineurin; Calcium; Calcium/calmodulin-dependent protein kinase; Calmodulin; Cardiac; Cell model; Cells; Cessation of life; Chronic; Clinical; Complex; Computer Simulation; Computer software; Cyclic AMP-Dependent Protein Kinases; Data; Databases; Dissection; Drug Formulations; Electrophysiology (science); Engineering; Faculty; Failure; Fluorescence Resonance Energy Transfer; Functional disorder; Gene Targeting; Genetic Engineering; Genetic Transcription; Genetically Engineered Mouse; Health; Heart; Heart failure; Histone Deacetylase; Hormonal; Human; Hypertrophy; In Vitro; Ions; Knock-out; Knockout Mice; Life; Link; Magnetic Resonance Imaging; Maps; Measurement; Measures; Mechanics; Microfilaments; Modeling; Molecular; Mus; Muscle Cells; Optics; Organ; Pathway interactions; Phenotype; Postdoctoral Fellow; Predisposition; Process; Proteins; Public Health; Pump; Regulation; Research Infrastructure; Research Personnel; Resource Sharing; Resources; Signal Transduction; Software Tools; Stimulus; Stress; Stretching; Structure; Students; Syndrome; System; Systems Biology; Testing; TimeLine; Tissues; Transgenic Mice; Transgenic Organisms; Universities; Validation; Ventricular; Virginia; calmodulin-dependent protein kinase II; cellular imaging; computer studies; data modeling; heart function; in vivo; in vivo Model; mouse model; multi-scale modeling; novel; overexpression; repository; research study; response; tissue preparation; tool; validation studies; ventricular hypertrophy; web site

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.

描述（由申请人提供）：心力衰竭是一个快速增长的健康问题，导致心律不齐或泵衰竭死亡。心肌细胞神经肿瘤调节，离子电流，钙（Ca2+）处理和收缩力的改变，并伴有心室肥大和结构重塑，都导致心力衰竭。了解这些复杂的生化和生物物理功能的相互作用需要定量系统模型，这些模型也可以在多个物理尺度上整合。需要良好的特征和容易扰动的实验系统来验证计算模型。现在有许多以基因为靶向的小鼠模型来概括心力衰竭的主要病理生理和临床特征。关于信号传导，电生理学，CA2+处理，肌丝功能和组织结构的变化的多尺度数据，无法在人类中获得的小鼠，但此处提出的新模型将提供一个系统的框架，以使发现型发现，以使发现构成对发现的发现。临床环境。 Ca2+ - 钙统治蛋白依赖性蛋白激酶（CAMKII）的上调和心力衰竭更为活跃，是导致急性机械和电气功能障碍以及心力衰竭慢性心脏重塑的细胞子系统的关键调节剂。 CAMKII的过表达导致小鼠心力衰竭，而CAMKII敲除或抑制可以防止失败。尽管其他途径也很重要，但我们在这里集中在小鼠模型上，其中多个关键心力衰竭表型都受CAMKII的无效或过表达影响。我们将利用实验室中正在进行的研究来扩展模型公式和验证所需的丰富实验数据集。 研究人员提出了新的实验和计算研究的紧密整合组合，利用PIS（UCD和McCulloch在UCSD的BERS）与戴维斯（Colleen Clancy and Leighton Izu）合作的PIS之间的强大跨学科协同作用（Joan Heller（Joan Heller）布朗和杰弗里·预兆）和弗吉尼亚大学（Jeffrey Saucerman）。该目的检验了我们的总体假设，即Ca2+ -CAMKII信号控制多个多尺度过程，这些过程在适应性的电生理学，CA2+处理，收缩和肥大性重塑方面协同作用，导致心力衰竭，包括：（1）2-肾上腺素受体和摄像头信号之间的串扰； （2）在亚细胞，细胞，组织和器官尺度上触发心律不齐的敏感性； （3）细胞，组织和器官尺度的心脏机械功能障碍； （4）响应压力的肥厚转录和不良适应性重塑。每个目标包括对新模型的制定和灵敏度分析，利用基因工程小鼠的验证研究以及对特定假设的测试。模型和数据将通过UCSD的国家生物医学计算资源支持，通过CellML存储库以及通过UC Davis Group开发的LabHeart软件工具的新版本来自由和广泛地利用软件和数据库基础架构。