Modeling of subcellular signaling crosstalk in failing myocytes

衰竭心肌细胞中亚细胞信号串扰的建模

• 批准号: 10192801
• 负责人: Stefano Morotti
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-15 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10192801
• 关键词: Action Potentials; Adrenergic Agents; Affect; Arrhythmia; Biochemical; Biological Models; Biological Process; Biophysics; Cardiac; Cardiac Myocytes; Cardiovascular system; Cavia; Cell Culture Techniques; Clinical; Complement; Complex; Computer Models; Confocal Microscopy; Coupling; Cyclic AMP-Dependent Protein Kinases; Data; Development; Disease; Electrophysiology (science); Ensure; Faculty; Feedback; Functional disorder; Future; Generations; Genetic Transcription; Goals; Growth; Guanine Nucleotide Exchange Factors; Health; Heart failure; Homeostasis; Hyperactivity; Impairment; In Vitro; Ion Transport; Ions; Link; Mathematical Model Simulation; Membrane; Mentors; Metabolic; Methods; Microfilaments; Mitochondria; Modeling; Muscle Cells; Nitric Oxide Synthase; Oryctolagus cuniculus; Oxidative Stress; Pathologic; Pathology; Pathway interactions; Pharmacology; Phase; Physiological; Positioning Attribute; Process; Production; Reactive Oxygen Species; Regulation; Research; Research Personnel; Research Project Grants; Research Proposals; Scheme; Seminal; Signal Pathway; Signal Transduction; Sodium; Supervision; Syndrome; System; Techniques; Testing; Therapeutic; Training; Transfection; Update; Variant; Ventricular; Workload; base; calmodulin-dependent protein kinase II; career; computer framework; computer studies; experimental study; heart function; in silico; innovation; inorganic phosphate; insight; mathematical model; mitochondrial dysfunction; multidisciplinary; novel; novel therapeutic intervention; porcine model; simulation; skills; skills training; targeted treatment; therapeutic evaluation; training opportunity

PROJECT SUMMARY/ABSTRACT. Heart failure (HF) is a rapidly growing health problem characterized by alterations in myocyte ion currents, Ca handling, contractile function and their neurohormonal regulation. Na dysregulation in HF is increasingly appreciated as a major, yet understudied aspect of cardiac function, linked to abnormal contraction, metabolic imbalance, and arrhythmia. By combining experimental and computational studies, this project aims to analyze quantitatively the contribution of various Na fluxes to the Na derangements in HF, and to link mechanistically intracellular Na dysregulation to mitochondrial function and cellular arrhythmias. Quantitative systems models that integrate across interacting biochemical and biophysical functions are essential for a mechanistic understanding of a complex clinical syndrome such HF, which involves multiple interacting systems. Here, we will develop the first integrative rabbit ventricular modeling framework including descriptions of intracellular Na and Ca handling, biochemically detailed models of Ca/calmodulin-dependent protein kinase II (CaMKII) and β-adrenergic signaling pathways, pH regulation, and mitochondrial function. The latter will be based on experimental data characterizing mitochondrial Ca handling and production of reactive oxygen species (ROS) in rabbit ventricular myocytes. The comprehensive model will be validated against a broad set of experimental data, and used to investigate how Na, Ca, CaMKII, ROS, and β-adrenergic signaling pathways contribute to (1) ionic remodeling in HF, (2) arrhythmia generation at the cellular level, and (3) metabolic imbalance. We will also test therapeutic approaches that target Na-related arrhythmias by specific inhibition of late Na current, CaMKII or ROS. Our study will provide enhanced mathematical models of these systems and substantially inform the development of pharmacological strategies. Moreover, the proposed project will significantly contribute to the personal and professional growth of the applicant. The first phase will provide an invaluable training opportunity, which will enhance the applicant’s competitiveness for faculty positions. Indeed, the proposed research plan will allow for acquisition of a broad interdisciplinary background in cardiac physio-pathology, refinement of computational skills, and training in new experimental techniques (i.e., cell culture and transfection, and confocal microscopy experiments). Completion of this training, under the supervision of an established and highly multidisciplinary mentoring team, will allow the applicant to diversify research goals and methods from those of his mentors, laying the groundwork for the development of future independent research projects and proposals. Continuation of the support during the second phase of the project will ensure the kick- off of the applicant’s independent academic career.

项目摘要/摘要。 心力衰竭 (HF) 是一种迅速发展的健康问题，其特征是肌细胞离子电流、Ca 的改变 处理、收缩功能及其神经激素调节。心力衰竭 (HF) 中的钠离子调节异常日益严重 被认为是心脏功能的一个主要但尚未得到充分研究的方面，与异常收缩、代谢 失衡和心律失常。通过结合实验和计算研究，该项目旨在分析 定量分析各种 Na 通量对 HF 中 Na 紊乱的贡献，并机械地联系起来 细胞内 Na 失调导致线粒体功能和细胞心律失常。 集成了相互作用的生化和生物物理功能的定量系统模型是 对于理解心力衰竭等复杂临床综合征的机制至关重要，该综合征涉及多种疾病 交互系统。在这里，我们将开发第一个综合兔心室建模框架，包括 细胞内 Na 和 Ca 处理的描述，Ca/钙调蛋白依赖性的生化详细模型 蛋白激酶 II (CaMKII) 和 β-肾上腺素信号通路、pH 调节和线粒体功能。这 后者将基于表征线粒体 Ca 处理和反应性产生的实验数据 兔心室肌细胞中的氧物质（ROS）。综合模型将根据 广泛的实验数据，用于研究 Na、Ca、CaMKII、ROS 和 β-肾上腺素能信号传导如何 通路有助于 (1) 心衰中的离子重塑，(2) 细胞水平上心律失常的产生，以及 (3) 代谢失衡。我们还将通过特定的方法测试针对钠相关心律失常的治疗方法 抑制晚Na电流、CaMKII或ROS。 我们的研究将为这些系统提供增强的数学模型，并为 药理学策略的开发。此外，拟议的项目将大大有助于 申请人的个人和职业成长。第一阶段将提供宝贵的培训 机会，这将增强申请人在教师职位上的竞争力。事实上，拟议的 研究计划将允许获得心脏生理病理学方面广泛的跨学科背景， 计算技能的提高以及新实验技术（即细胞培养和 转染和共焦显微镜实验）。在培训师的监督下完成本次培训 建立的高度跨学科的指导团队，将使申请人能够实现研究目标的多样化 借鉴导师的方法，为以后独立研究的发展奠定了基础 项目和建议。项目第二阶段的持续支持将确保项目的启动 脱离申请人的独立学术生涯。