This program Project Grant (PPG) proposal comprises four Projects and two Cores. The focus of the projects is identification of molecular signaling that initiate fatal cardiac arrhythmias (Sudden Cardiac Death SCD). A central hypotheses is that adrenergic modulation of ion channels perturbs intracellular Ca signaling leading to triggers of SCD. We propose that perturbations of intracellular calcium homeostasis, primarily due to defective regulation of the ion channels including potassium, sodium, calcium channels as well as the ryanodine receptor/calcium release channel on the cardiac sarcoplasmic reticulum, initiate, initiate triggers of fatal cardiac arrythmias. Each of the proposed projects requires extensive work with animal models which will be supported by the following core. The present core will provide support for the projects in four major areas: (a) the preparation and maintenance of transgenic and knockout mice and (b) Characterization of transgenic and knock-out mice including preparation and analysis of tissue specimens from animals (c) Physiological measurements on transgenic and knockout mice including drug testing and (d) Characterizing B adrenergic receptor signaling in the normal and transgenic mouse hearts.
| Kushnir, Alexander; Santulli, Gaetano; Reiken, Steven R et al. (2018) Ryanodine Receptor Calcium Leak in Circulating B-Lymphocytes as a Biomarker in Heart Failure. Circulation 138:1144-1154 |
| Zalk, Ran; Marks, Andrew R (2017) Ca2+ Release Channels Join the 'Resolution Revolution'. Trends Biochem Sci 42:543-555 |
| Williams, George S B; Boyman, Liron; Lederer, W Jonathan (2015) Mitochondrial calcium and the regulation of metabolism in the heart. J Mol Cell Cardiol 78:35-45 |
| Santulli, Gaetano; Pagano, Gennaro; Sardu, Celestino et al. (2015) Calcium release channel RyR2 regulates insulin release and glucose homeostasis. J Clin Invest 125:1968-78 |
| Drum, Benjamin M L; Santana, Luis F (2015) The long and winding road home: how junctin and triadin find their way to the junctional SR. J Mol Cell Cardiol 81:15-7 |
| Greiser, Maura; Kerfant, Benoît-Gilles; Williams, George S B et al. (2014) Tachycardia-induced silencing of subcellular Ca2+ signaling in atrial myocytes. J Clin Invest 124:4759-72 |
| Boyman, Liron; Chikando, Aristide C; Williams, George S B et al. (2014) Calcium movement in cardiac mitochondria. Biophys J 107:1289-301 |
| Ward, Christopher W; Prosser, Benjamin L; Lederer, W Jonathan (2014) Mechanical stretch-induced activation of ROS/RNS signaling in striated muscle. Antioxid Redox Signal 20:929-36 |
| Rullman, Eric; Andersson, Daniel C; Melin, Michael et al. (2013) Modifications of skeletal muscle ryanodine receptor type 1 and exercise intolerance in heart failure. J Heart Lung Transplant 32:925-9 |
| Mannella, Carmen A; Lederer, W Jonathan; Jafri, M Saleet (2013) The connection between inner membrane topology and mitochondrial function. J Mol Cell Cardiol 62:51-7 |
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