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.

项目总结/摘要。 心力衰竭（HF）是一种快速增长的健康问题，其特征是肌细胞离子电流（Ca 处理、收缩功能和它们的神经激素调节。HF中的Na调节异常越来越多地 被认为是心脏功能的一个主要方面，但研究不足，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 定量地分析了各种Na通量对HF中Na无序的贡献，并从机理上将其联系起来。 线粒体功能和细胞心律失常的细胞内Na调节异常。 整合了相互作用的生物化学和生物物理功能的定量系统模型， 对于复杂临床综合征（如HF）的机制理解至关重要，HF涉及多个 互动系统在这里，我们将开发第一个集成的兔心室建模框架，包括 细胞内Na和Ca处理的描述，Ca/钙调素依赖的生化详细模型 蛋白激酶II（CaMKII）和β-肾上腺素能信号传导途径、pH调节和线粒体功能。的 后者将基于表征线粒体Ca处理和反应性钙的产生的实验数据。 氧自由基（ROS）。综合模型将根据 广泛的实验数据集，并用于研究Na，Ca，CaMKII，ROS和β-肾上腺素能信号传导 通路有助于（1）HF中的离子重塑，（2）细胞水平的心律失常产生，和（3） 代谢失衡我们还将通过特定的方法来测试针对钠相关心律失常的治疗方法。 抑制晚期Na电流、CaMK II或ROS。 我们的研究将为这些系统提供增强的数学模型，并为研究人员提供大量信息。 药理学策略的发展。此外，拟议项目将大大有助于 申请人的个人和专业成长。第一阶段将提供宝贵的培训 机会，这将提高申请人的竞争力的教师职位。事实上，拟议的 研究计划将允许在心脏生理病理学方面获得广泛的跨学科背景， 计算技能的改进，以及新实验技术的培训（即，细胞培养和 转染和共聚焦显微镜实验）。在一名负责人的监督下完成本培训 建立和高度多学科的指导团队，将允许申请人多样化的研究目标， 方法从那些他的导师，奠定了基础，为未来的独立研究的发展 项目和提案。在项目第二阶段继续提供支持将确保启动- 申请人的独立学术生涯。