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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.

项目总结/抽象。

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

Quantitative systems models illuminate arrhythmia mechanisms in heart failure: Role of the Na+ -Ca2+ -Ca2+ /calmodulin-dependent protein kinase II-reactive oxygen species feedback.

定量系统模型阐明了心力衰竭的心律失常机制：Na -Ca2 -Ca2 /钙调蛋白依赖性蛋白激酶 II - 活性氧反馈的作用。

DOI：
10.1002/wsbm.1434
发表时间：
2019
期刊：
Wiley interdisciplinary reviews. Systems biology and medicine
影响因子：
0
作者：
Morotti,Stefano;Grandi,Eleonora
通讯作者：
Grandi,Eleonora

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