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. (A) OBJECTIVES Abnormal structural remodeling causes mal-adaptive responses of the heart to mechanical and humeral stresses (2). Based on our previous published studies and results from our preliminary works, we propose that Z-disc defects are central to such pathological processes, resulting in the progression of malignant congestive heart failure, and hypothesize that two major pathways are involved. One is the dysfunction of Z-disc-linked molecular sensors for mechanical stresses and the other is the secondary disorganization of membrane organelles, namely transverse tubules (T-tubules), junctional sarcoplasmic reticulum (jSR), and dyads, which are all located in the vicinity of Z-discs and are physically linked to them. These membrane organelles are known to play a major role to dynamically control cellular calcium levels, which in turn regulates cardiac contraction (3). The main objectives of this project are: (1) to improve microscopic visualization of cardiac organelles by applying computational tools prepared by the NBCR to advanced electron and light microscopic (EM/LM) technologies;and (2) to establish multi-scale three-dimensional anatomical models of cardiac Z-discs and associated membrane organelles that will be used to simulate path-physiological sequences of cardiac regulations, based on experimental data, in normal and remodeled cardiac Z-discs and vicinal membrane micro-domains.
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