MESOSCALE MODELING OF CARDIAC CALCIUM-INDUCED CALCIUM-RELEASE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 这个合作项目的目标是进行一项实验和模型相结合的研究，研究钙信号(钙信号，我们称为钙释放微域(CCRM))如何影响心肌细胞钙诱导钙释放(CICR)的特性。我们粗略地将CCRM定义为由心脏二分体、相邻的解剖结构(例如横管：T管和连接肌浆网：JSR)和细胞器(例如线粒体)组成，这些结构足够接近二分体(在数百纳米范围内)，从而可能影响局部CICR。我们将使用优化的工具和技术来实现CCRM结构的三维(3D)断层电子显微镜(EM)成像，包括绘制离子通道和交换器的位置，例如L类型的钙通道(LCC)、2型ryanodine受体(RyR2)、Na-Ca交换器(NCX1)、Na-K ATPase(NKA)和2型1，4，5-三磷酸肌醇受体(InsP3Rs)。我们将利用这些结构数据来开发一个基于实验的心脏CCRM的结构和生物物理详细模型。该模型将被用来研究CCRM结构和通道布局对CICR的作用。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The objective of this collaborative project is to undertake a combined experimental and modeling study investigating how calcium (Ca2+) signaling, in what we refer to as the Ca2+-release microdomain (CCRM), influences properties of calcium-induced calcium-release (CICR) in the cardiac myocyte. We loosely define the CCRM as consisting of the cardiac ¿¿dyad,¿¿ adjacent anatomic structures (e.g., transverse tubules: T-tubules, and junctional sarcoplasmic reticulum: jSR), and organelles (e.g., mitochondria), which are sufficiently close to the dyad (within several hundred nanometers) that they may influence local CICR. We will use tools and techniques optimized to achieve three-dimensional (3D) tomographic electron microscopic (EM) imaging of CCRM structures, including mapping of the locations of ion channels and exchangers, such as L-type Ca2+ channels (LCCs), type 2 ryanodine receptors (RyR2s), the Na+-Ca2+ exchanger (NCX1), the Na+-K+ ATPase (NKA), and type 2 inositol 1,4,5-trisphosphate receptors (InsP3Rs). We will utilize these structural data to develop an experiment-based structurally and biophysically detailed model of cardiac CCRM. The model will be used to investigate the role of CCRM structure and channel placement on CICR.