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 initial objective of Project 4 was to use both in vivo and ex vivo animal models to delineate the role of Cl- channels in normal and diseased hearts. To address the specific aims we have established multiple approaches to the assessment of cardiac function in animal models of myocardial ischemia and reperfusion, ischemia preconditioning (IPC), and pressure overload-induced hypertrophy and heart failure in both wild-type (WT) and genetically-engineered (GE) mice. We have provided compelling evidence for the functional role of Cl- channels in cardiac disease and protection and have set up the stage for further elucidation of the underlying cellular and molecular mechanisms. We now hypothesize that Cl- channels in the heart may function as integrated multiprotein complexes, which belong to distinct Cl- channel subproteomes and may be composed of pore forming subunit for ion transportation, auxiliary subunits for modulating pore gating, and proteins as second messengers tightly coupled to channel function, and dysfunction of the functional Cl- channel complex play important role in heart diseases. We will use functional genomic and proteomic strategies and technologies to identify specific genomic and proteomic changes in each Cl- channel complexes responsible for the genesis of a physiological or pathophysiological phenotype. In close collaboration with Projects 1 and 5, we will apply the established in vivo and ex vivo animal models to the recently created heart-specific conditional or inducible ClC-3-/-, hsClcn3+/+ and hlClcn3+/+ mice to delineate the role and mechanism of the volume-regulated ClC-3 channel complex in cardiac disease and IPC at whole animal, isolated organ, and single cell levels. We also will study the functional role of Ca2+-activated Cl- channels in heart in close collaboration with Project 3 using mice targeting cardiac Bestrophin or CLCA1 (Core A). We will address the following specific aims and questions: 1) What is the role of volume-regulated Cl- channel complex (ClC-3 subproteome) and the Ca2+-activated Cl- channel complex (CLCA1 or Bestrophin subproteome) in normal cardiac electrophysiology and hemodynamics? 2) What is the mechanism for the functional role of cardiac Cl- channel complexes (ClC-3, CLCA1 and Bestrophin, respectively) in myocardial hypertrophy and heart failure? 3) What is the role and mechanisms of ClC-3, CLCA1, and Bestrophin in ischemia and reperfusion induced arrhythmia? 4) What is the mechanism for the role of ClC-3, CLCA1, and Bestrophin in cardiac IPC? Our study in this research proposal will provide crucial knowledge for the development of new specific anion channel-selective drugs for heart diseases such as arrhythmias, ischemia, and heart failure.
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