MESOSCALE MODELING OF CARDIAC CALCIUM-INDUCED CALCIUM-RELEASE

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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.