Image-Based Modeling of Ca2+ Signaling in Ventricular Myocytes

描述（由申请人提供）：钙是细胞中最通用的生物信使之一，在调节细胞功能中起着关键作用。特别是，心肌细胞（肌细胞）中钙浓度的瞬时变化形成了细胞范围收缩的基础，最终导致整个心脏收缩。因此，研究心肌细胞中的钙信号是理解细胞中的兴奋-收缩（E-C）偶联并最终揭示心脏疾病的微观机制的基础研究课题。本提案的主要目标是利用三维（3D）电子显微镜（EM）图像和数学模拟技术来探索基于图像的心室肌细胞钙信号建模，以实现对心脏病微观环境的现实理解。所提出的研究的具体目标是：（A）从先进的三维EM成像数据构建逼真的几何模型。将开发和实施有效的图像处理、分析和几何建模的计算方法，以提取感兴趣的亚细胞结构，并构建高保真、高质量的表面和体积网格，这些网格将用于随后的数学模拟。(B)使用随机和确定性方法表征钙信号。我们将探讨如何使用蒙特卡罗方法在单个CRU内/周围形成单一钙释放事件（即钙火花）。从3D EM图像中提取的解剖模型将用于指定模拟域。此外，将采用有限元（确定性）方法研究CRU中的钙信号（波），其中将使用从高级3D EM图像中提取的逼真几何模型指定模拟域。将研究正常和患病的心室肌细胞。(C)开发图形用户界面（GUI），以简化生物医学图像的解剖建模和可视化。将创建一个用户友好的GUI来封装用于图像处理、特征提取和网格生成的所有计算模块。该工具包用于简化从2D/3D图像到3D解剖模型的多个计算过程，并将提供给生物医学界。 公共卫生相关性：心力衰竭是包括美国在内的许多国家人类死亡的主要原因之一。这种疾病的流行主要是由于我们缺乏对心肌细胞兴奋-收缩（E-C）偶联的准确理解。钙信号的计算机和数学建模一直是实现这一目标的重要途径。这项研究将使我们能够使用从3D成像数据中提取的结构信息来模拟钙信号，这将为心脏病的机制提供更真实和准确的理解。

DESCRIPTION (provided by applicant): Calcium has been one of the most versatile biological messengers in a cell, playing critical roles in regulating the cell's functions. In particular, the transient change of calcium concentration in cardiac muscle cells (myocytes) forms the basis of cell-wide contraction that eventually results in the whole heart contraction. Studying calcium signaling in cardiac myocytes is thus a fundamental research topic in understanding the excitation-contraction (E-C) coupling in the cells and ultimately revealing the microscopic mechanism of heart disease. The main goal of the present proposal is to utilize three-dimensional (3D) electron microscopic (EM) images and mathematical simulation techniques to explore image-based modeling of calcium signaling in ventricular myocytes to achieve a realistic understanding of the microscopic environment of heart disease. The specific aims of the proposed studies are: (A) Constructing realistic geometric models from advanced 3D EM imaging data. Efficient computational approaches of image processing, analysis and geometric modeling will be developed and implemented to extract the sub-cellular structures of interest and to construct high-fidelity, high-quality surface and volumetric meshes that will be used in the subsequent mathematical simulation. (B) Characterizing calcium signaling using both stochastic and deterministic methods. We shall explore how unitary calcium release events (i.e. calcium sparks) are formed within/around a single CRU using the Monte Carlo method. Anatomical models extracted from 3D EM images will be used to specify the simulation domains. In addition, finite element (deterministic) methods will be employed to investigate the calcium signaling (waves) across CRUs, where the simulation domains will be specified with realistic geometric models extracted from advanced 3D EM images. Both normal and diseased ventricular myocytes will be investigated. (C) Developing a graphical user interface (GUI) to streamline anatomical modeling and visualization of biomedical images. A user-friendly GUI will be created to encapsulate all the computational modules for image processing, feature extraction, and mesh generation. This toolkit is made to streamline multiple computational processes from 2D/3D images to 3D anatomical models and will be made available to the biomedical community. PUBLIC HEALTH RELEVANCE: Heart failure has been one of the leading causes of human deaths in many countries including the United States. The prevalence of this disease is largely due to our lack of accurate understanding of excitation-contraction (E-C) coupling in cardiomyocytes. Computer and mathematical modeling of calcium signaling has been an important way to achieve this goal. The proposed study will enable us to model calcium signaling using the structural information extracted from the 3D imaging data, which would provide a more realistic and accurate understanding of the mechanism of heart disease.