Core B is the long-term objective of the Mouse Cardiac Physiology Core is to consolidate the scientific and technical expertise and the specialized equipment necessary to provide: a) standardized, high-quality, and appropriate microsurgery for the induction of chronic heart failure in mice; and b) rigorous, reliable, and accurate in vivo assessment of mouse cardiac physiology. All four projects proposed in this Program Project Grant rely heavily on mouse models of heart failure to test hypotheses about regulatory mechanisms of cardiomyocyte calcium channels in health and cardiac disease. Excitation-contraction coupling, contractility, and cardiac remodeling all require the intricate regulation and coordination of cardiomyocyte calcium channel subunits and their interactomes. Even as investigators focus on studying human loss of function variants, genetically modified mice are indispensable to deciphering the regulatory function of the gene variants. Given that, at times, cardiac genotype-phenotype associations are evidenced only under stress conditions, it will be imperative to examine cardiac structure and function of transgenic mice under baseline conditions and following chronic cardiac stress. As such, the Mouse Cardiac Physiology Core will address three specific aims:
-
Performing survival microsurgeries on mice to induce either chronic pressure-overload or chronic ischemic stress upon the left ventricle. This will be accomplished through transverse aortic constriction and left coronary artery ligation, respectively.
-
Assessing in vivo cardiac structure and function of experimental mice over time via serial echocardiograms.
-
Determining the left ventricular pressure-volume relationship using in vivo invasive conductance catheter measurements.
By streamlining these essential procedures and analyses, the Mouse Cardiac Physiology Core will accelerate the pace at which our Investigators obtain invaluable insights into the structure and function of calcium channel complexes in cardiac physiology and disease. Thus ,our work in the Mouse Cardiac Physiology Core will be synergistic with that of the four individual program projects and the Human Phenotyping Core. We expect that our cumulative findings will identify clinically relevant regulatory mechanisms and structure-function relationships that can then facilitate novel therapeutic developments and interventions.