Our group undertakes research in several major areas, which are summarized below. A bidirectional information flow between experiments and simulations is central to our research program: experimental data serves to complement the hypotheses tested by our simulations, and the high-resolution predictions from our simulations provide new hypotheses to test in the laboratory.
Heart failure drug discovery
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Despite substantial advances in the clinical management of heart failure (HF), the diagnosis continues to carry a grave prognosis, with an overall 5-year mortality rate of approximately 50%. A key molecular dysfunction in HF involves insufficient calcium transport needed to relax muscle cells in each heart beat (diastole), usually associated with impaired activity of SERCA. In our group, we use complementary computational methods, and in vitro/in vivo experiments to discover and develop novel molecules that reactivate SERCA in the failing heart. This complementary approach offers a new way to increase screening precision, to shorten the timeline to discover hit molecules, and to decrease the costs involved with HF drug development.
Novel mechanisms for SERCA dysregulation in obesity
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Diet-induced obesity is a major risk factor for cardiac arrhythmias. Indeed, there is evidence indicating that obese individuals have ~50% increased risk compared to non-obese patients, and obese young men have more than a 2-fold risk of arrhythmias compared with young men of normal weight. Clinical studies have associated increased body mass index with arrhythmias, where every unit increase in body mass index (BMI) increases the development of them by up to 8%. The pathophysiological and molecular mechanisms associated with arrhythmias are complex and the molecular basis for this association remains unclear. We address these mechanisms by using animal models of diet-induced obesity in combination various experimental techniques. Studies in our group have revealed new links between obesity, altered SERCA-mediated calcium signaling, and atrial fibrillation.
Development of in silico drug design methodologies
Hit-to-lead optimization is a challenging and often resource-intensive phase of lead discovery, so the early and less costly elimination of undesirable or intractable lead classes is of significant value before extensive medicinal chemistry efforts are initiated. We develop computational approach that predicts and maps favorable and unfavorable chemical fragments around a validated hit molecule for the accurate design of lead molecules, thus greatly reducing the costs associated with brute-force chemical synthesis and functional tests. This computational approach integrates molecular docking and dynamics, chemical space mining tools, and data analysis models into comprehensive pattern recognition algorithms.
Regulation of calcium uptake into the sarco/endoplasmic reticulum
SR calcium uptake in cells is regulated by a family of small transmembrane proteins. These proteins include phospholamban (PLB) and sarcolipin (SLN), which bind to SERCA and regulate its activity in cardiac and skeletal muscle. We study in atomic-level detail the mechanisms for PLB- and SLN-mediated SERCA inhibition, reactivation and uncoupling. We extend these studies to include novel regulatory micropeptides, such as endoregulin and another-regulin, which inhibit the activity of SERCA isoforms that are abundant in non-muscle cells. The goal of our research is to provide a consensus mechanism for control of SERCA function, thus gleaning real mechanistic insights into SERCA regulation in the cell.