Modeling Spatial Organization of Cardiac Cell Function: Application to Calcium Waves and Arrhythmia

0929633Rudy本申请的长期目标是将空间维度引入心脏动作电位和钙循环模型，并开发新的建模工具，用于解决有关心律失常细胞起源的未回答问题。具体而言，钙依赖性信号通路对钙循环和心脏动作电位的时间和空间动态特性的局部（亚细胞）效应的机制将被研究。该模型将考虑钙扩散，从而允许模拟钙波及其对细胞电生理学的促凋亡作用。该模型将首次提供用于模拟实验钙荧光图像和用于从这些图像重建实际钙瞬变的理论工具。利用这个模型，钙波的启动和传播的机制，它们通过信号通路活动的调节，以及它们在异常动作电位复极和致心律失常后去极化中的作用将被研究。从科学的角度来看，它旨在通过纳入细胞结构的重要元素，将心脏细胞的数学模型带到下一个生理细节水平。所提出的模型采取了重要的后续步骤，将空间维度和钙依赖性信号通路纳入细胞模型。从医疗保健的角度来看，越来越多的证据表明，钙波动力学是心力衰竭患者和携带参与钙循环的蛋白质突变的个体中危及生命的心律失常和心源性猝死的基础。数学建模将为这些过程提供机械的见解，这些过程对于开发新的有效的诊断，预防和治疗方法至关重要。最后，从教育的角度来看，他们的细胞模型已被广泛用于许多机构，作为工程学，生理学，生物物理学和药理学的教学和开发工具，并用于培训各级医生和科学家（医学生，居民和研究员专门从事心脏电生理学和心律失常）。添加亚细胞空间组织及其在细胞功能中的主要作用将显着增强这些学习经验。虽然该提议集中于心脏细胞，但钙子系统的空间组织、钙信号传导和钙波是其他肌肉系统（包括骨骼肌和平滑肌细胞）中细胞兴奋和收缩的重要组成部分。结合这些特性的心脏细胞模型的制定可以作为这些其他肌肉系统的范例。对于心脏研究界来说，这类新的细胞模型将提供细胞构建模块，用于以多尺度方法整合到更高层次的组织（多细胞组织，整个心脏）中，以研究心脏电生理学和心律失常。学生和研究员将接受心脏细胞建模的培训。为此，并为方便其他实验室和学术机构使用模型，将在网站上全面提供根据本建议在Matlab平台上开发的模型，并提供实施方面的协助。

0929633RudyThe long-term goal of this application is to introduce the spatial dimension into models of the cardiac action potential and calcium cycling and to develop new modeling tools that will be used to address unanswered questions regarding the cellular origins of cardiac arrhythmias. Specifically, the mechanisms that underlie the local (subcellular) effects of the calcium-dependent signaling pathways on the temporal and spatial dynamic properties of calcium cycling and the cardiac action potential will be studied. The model will account for calcium diffusion, thus allowing for simulation of calcium waves and their arrhythmogenic effects on the cell electrophysiology. This model will provide, for the first time, a theoretical tool for simulating experimental calcium fluorescence images and for reconstructing from these images the actual calcium transients. Using this model, the mechanism of calcium - wave initiation and propagation, their modulation by signaling pathways activity, and their role in abnormal action potential repolarization and arrhythmogenic afterdepolarizations will be investigated.The proposed project encompasses several strata of intellectual merit. From a scientific perspective, it is aimed at bringing mathematical models of cardiac cells to the next level of physiological detail by incorporating important elements of cell architecture. The proposed model takes the important next steps of incorporating the spatial dimension and calcium-dependent signaling pathways in the cell models. From the healthcare perspective, there is increasing evidence that calcium wave dynamics underlie life threatening arrhythmias and sudden cardiac death in heart failure patients and in individuals who carry mutations in proteins that participate in calcium cycling. Mathematical modeling will provide mechanistic insights into these processes that are essential for developing novel effective approaches to diagnosis, prevention and treatment. Finally, from the educational perspective, their cell models have been used extensively in many institutions as teaching and developing tools in engineering, physiology, biophysics and pharmacology, and for training physicians and scientists at various levels (medical students, residents, and fellows specializing in cardiac electrophysiology and arrhythmia). Adding the sub-cellular spatial organization and its major role in cell function will enhance significantly these learning experiences. While this proposal focuses on cardiac cells, spatial organization of the calcium subsystem, calcium signaling and calcium waves are essential components of cell excitation and contraction in other muscle systems, including skeletal and smooth muscle cells. Formulation of a cardiac cell model that incorporates these properties could serve as a paradigm for these other muscle systems. For the cardiac research community, the new class of cell models will provide cellular building blocks for integrating into higher levels of organization (multicellular tissue, whole heart) in a multi-scale approach for studying cardiac electrophysiology and arrhythmia. The students and fellows will be trained in cardiac cell modeling. To this end, and to facilitate use of the models by other laboratories and academic institutions, the models developed under this proposal in the Matlab platform with Interactive Graphical User Interface will be fully available on the website and assistance for their implementation will be provided.