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

基本信息

批准号：
10414793
负责人：
Stefano Morotti
金额：
$ 22.41万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-15 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10414793
关键词：
Action Potentials Adrenergic Agents Affect Arrhythmia Biochemical Biological Models Biological Process Biophysics Cardiac Cardiac Myocytes Cardiovascular system 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 guinea pig model heart function in silico innovation inorganic phosphate insight mathematical model mitochondrial dysfunction multidisciplinary novel novel therapeutic intervention simulation skills skills training targeted treatment therapeutic evaluation training opportunity

项目摘要

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）是一个快速增长的健康问题，其特征是肌细胞电流的改变，CA 处理，收缩功能及其神经激素调节。 HF中的NA失调越来越多被认为是主要的，但知识的心脏功能方面，与异常收缩，代谢有关不平衡和心律不齐。通过结合实验和计算研究，该项目旨在分析定量地，各种NA通量对HF中的NA演变的贡献，并机械地链接细胞内NA对线粒体功能和细胞心律不齐的失调。跨相互作用的生化和生物物理功能整合的定量系统模型是对复杂临床综合征这样的HF的机械理解至关重要，该综合征涉及多个交互系统。在这里，我们将开发第一个综合兔子心室建模框架，包括细胞内NA和CA处理的描述，CA/CALIDULIN依赖性依赖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。后者将基于表征线粒体CA处理和产生反应性的实验数据兔心肌细胞中的氧（ROS）。综合模型将与广泛的实验数据集，并用于研究Na，Ca，CaMkII，ROS和β-肾上腺素信号传导如何途径有助于（1）HF中的离子重塑，（2）在细胞水平上产生心律失常，（3）代谢失衡。我们还将测试针对NA相关心律不齐的治疗方法抑制晚期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，并实质上告知制定药物策略。此外，拟议的项目将对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，这将增强申请人在教师职位上的竞争力。确实，提议研究计划将允许获取心脏生理学的广泛跨学科背景，对计算技能的完善和新实验技术的培训（即细胞培养和转染和共聚焦显微镜实验）。在一个培训的完成下完成建立且高度多学科的指导团队将使申请人能够多元化研究目标和他的导师的方法为发展未来独立研究的发展奠定了基础项目和建议。在项目的第二阶段继续支持支持将确保踢球不在申请人的独立学术生涯中。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Mechanisms of spontaneous Ca2+ release-mediated arrhythmia in a novel 3D human atrial myocyte model: II. Ca2+ -handling protein variation.

新型 3D 人心房肌细胞模型中自发 Ca2 释放介导的心律失常的机制：II。

DOI：
10.1113/jp283602
发表时间：
2023
期刊：
The Journal of physiology
影响因子：
0
作者：
Zhang,Xianwei;Smith,CharlotteER;Morotti,Stefano;Edwards,AndrewG;Sato,Daisuke;Louch,WilliamE;Ni,Haibo;Grandi,Eleonora
通讯作者：
Grandi,Eleonora

GRK5 Controls SAP97-Dependent Cardiotoxic β1 Adrenergic Receptor-CaMKII Signaling in Heart Failure.

GRK5 控制心力衰竭中 SAP97 依赖性心脏毒性β1 肾上腺素受体-CaMKII 信号传导。

DOI：
10.1161/circresaha.119.316319
发表时间：
2020
期刊：
Circulation research
影响因子：
20.1
作者：
Xu,Bing;Li,Minghui;Wang,Ying;Zhao,Meimi;Morotti,Stefano;Shi,Qian;Wang,Qingtong;Barbagallo,Federica;Teoh,Jian-Peng;Reddy,GopireddyR;Bayne,ElizabethF;Liu,Yongming;Shen,Ao;Puglisi,JoseL;Ge,Ying;Li,Ji;Grandi,Eleonora;Nieve
通讯作者：
Nieve

A Heart for Diversity: Simulating Variability in Cardiac Arrhythmia Research.

DOI：
10.3389/fphys.2018.00958
发表时间：
2018
期刊：
Frontiers in physiology
影响因子：
4
作者：
Ni H;Morotti S;Grandi E
通讯作者：
Grandi E

Sex-Specific Classification of Drug-Induced Torsade de Pointes Susceptibility Using Cardiac Simulations and Machine Learning.

DOI：
10.1002/cpt.2240
发表时间：
2021-08
期刊：
Clinical pharmacology and therapeutics
影响因子：
6.7
作者：
Fogli Iseppe A;Ni H;Zhu S;Zhang X;Coppini R;Yang PC;Srivatsa U;Clancy CE;Edwards AG;Morotti S;Grandi E
通讯作者：
Grandi E

Editorial: Safety Pharmacology - Risk Assessment QT Interval Prolongation and Beyond.