MESOSCALE MODELING OF CARDIAC CALCIUM-INDUCED CALCIUM-RELEASE

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 研究中心，而研究中心不一定是研究者所在的机构。 该合作项目的目的是进行一项综合实验和建模研究，研究钙（Ca 2+）信号传导（我们称之为Ca 2+释放微域（CCRM））如何影响心肌细胞中钙诱导钙释放（CICR）的特性。我们将CCRM粗略定义为由心脏 二进制，邻近的解剖结构（例如，横小管：T-小管，和连接肌浆网：jSR），和细胞器（例如，线粒体），其足够接近二分体（在几百纳米内），它们可能影响局部CICR。我们将使用优化的工具和技术来实现CCRM结构的三维（3D）断层扫描电子显微镜（EM）成像，包括离子通道和交换剂位置的映射，例如L型Ca 2+通道（LCC），2型ryanodine受体（RyR 2s），Na+-Ca 2+交换剂（NCX 1），Na+-K+ ATP酶（NKA）和2型肌醇1，4，5-三磷酸受体（InsP 3Rs）。我们将利用这些结构数据来开发一个基于实验的心脏CCRM结构和生物病理学详细模型。该模型将被用来调查的作用，CCRM的结构和渠道布局的CICR。

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.