The overall goal of the research proposed in this program project application is to identify thecellular and molecular triggers that initiate fatal cardiac arrhythmias and to determine novelmolecular-targeted therapeutic strategies to treat them. The central hypothesis is that suddencardiac death (SCD) can be caused by disruption of molecular complexes and processes that, innormal hearts, underlie balanced regulation of cellular activity and furthermore that altered cellularcalcium homeostasis plays a critical role in triggering the resulting arrhythmic activity. It is thus thefundamental assumption of this program that, to understand the mechanistic basis of the eventsthat underlie SCD, an integrative approach is necessary that identifies molecular defects of ionchannel complexes that coordinate the function of intracellular (Project 1) and plasma membrane(sarcolemmal) (Project 2) ion channels as well as interaction with and dysregulation of intracellularcalcium regulation (Project 3). This project focuses on the roles of key sarcolemmal ionic currentsin the generation of abnormal calcium-dependent electrical instability. Experiments that areproposed combine patch clamp measurement of ion channel activity, and intracellular calcium andsodium concentrations in myocytes isolated from genetically-altered mice. There are two specificaims.
The first aim i s to determine whether mutations in sarcolemmal Na+ channels linked to SCDcontribute to spontaneous diastolic calcium-dependent electrical activity. The principal hypothesisof this aim is that sustained Na+ entry via mutation-enhanced late sodium channel currentspromotes abnormal calcium-dependent diastolic activity due to a combination of action potentialprolongation, increased SR Ca load and extrusion of intracellular calcium during diastole.
The second aim i sjo investigate mechanisms whereby sympathetic nervous system activationcontributes to arrhythmias that can cause SCD. The hypothesis to be tested is that adrenergicstimulation (AS) increases ITI susceptibility in part by combined effects of sustained INa (INaL), and enhanced SR Ca load and leak, providing a mechanism whereby increased sympathetic nervous system (SNS) activity can be pro-arrhythmogenic in the context of sustained INa (INaL) (e.g. as seen in heart failure (chronic AS) and in patients with AKPQ mutations in Nav1.5 (transient AS). The proposed studies are significant because they may provide a mechanism whereby altered plasmalemmal Na channel activity can cause calcium dependent cardiac arrhythmias may lead to novel therapeutic concepts for anti-arrhythmic therapy.
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| Zalk, Ran; Marks, Andrew R (2017) Ca2+ Release Channels Join the 'Resolution Revolution'. Trends Biochem Sci 42:543-555 |
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| 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 |
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| 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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