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Address: 1216 MERF
Phone: (319) 335-8303
Mentor: Mark E. Anderson, MD, PhD
Undergraduate Institution: Washingon and Lee University, BS
Year Entered Into Program: 2009 (MSTP) 2011 (PhD Program)
Cardiovascular disease is the leading cause of death in the United States and represents a massive public health burden. Many cardiac conditions remain difficult to treat and new interventions are needed. Recent studies have identified mitochondrial dysfunction (mitochondrial membrane derangements, decreased ATP production, increased ROS production) to be a prominent feature of cardiovascular diseases, including atrial fibrillation (AF), the most common clinical arrhythmia. The molecular signals resulting in mitochondrial dysfunction remain unclear and it is unknown if the prevention of mitochondrial dysfunction might protect the heart from AF. To this end, the Anderson lab has been investigating the mitochondrial signaling role of the molecule Ca2+/calmodulin-dependent protein kinase II (CaMKII) in the setting of AF. Our group identified a mechanism for CaMKII activation by oxidation of paired Met residues (281/282) in the CaMKII regulatory domain, and has established that this oxidation locks oxidized CaMKII (ox-CaMKII) into a persistently active configuration, which leads to pathological remodeling in ventricles after Ang-II infusion and myocardial infarction. The role of ox-CaMKII in atrial disease has yet to be established. Recently, we found that expression of ox-CaMKII is increased in atria from AF patients compared to controls. This led to the development and validation of a mouse model of Ang-II infusion and enhanced AF susceptibility. We found that Ang II-infused, AF-susceptible mice resembled AF patients by having increased atrial expression of ox-CaMKII, leading to the hypothesis that ox-CaMKII is involved in molecular, cellular and tissue mechanisms favoring AF. New data from our lab show that increased ox-CaMKII, an apparent feature of AF, causes a loss of mitochondrial ultrastructure, promotes apoptosis and leads to tissue fibrosis. Specifically, ox-CaMKII appears to promote the opening of the mitochondrial calcium uniporter, leading to increased mitochondrial calcium flux. Several lines of evidence point to excessive Ca2+ entry as a critical mediator of mitochondrial dysfunction in AF, but what is lacking is an understanding of a molecular framework that regulates mitochondrial Ca2+ entry in diseases such as AF. Currently, I am investigating the interaction between ox-CaMKII and mitochondrial calcium handling in mouse models of AF, specifically whether pharmacological and genetics-based approaches targeted to mitochondria and against ox-CaMKII can alter the susceptibility to atrial arrhythmias.
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