Our lab seeks to characterize physiological adaptations to stress and identify novel therapeutic targets in cardiovascular and metabolic illness.
Regulation of Endogenous Hydrogen Sulfide Signaling
A portion of our research efforts focuses on the ability of hydrogen sulfide, an endogenously produced gasotransmitter, to activate cytoprotective-signaling cascades in the setting of acute myocardial ischemia and in the setting of heart failure. Our work has resulted in the demonstration that the administration of hydrogen sulfide donors either prior to ischemia or after reperfusion significantly ameliorates in vivo myocardial ischemia-reperfusion injury in mice with a clear reduction in myocardial infarction, oxidative stress, apoptosis, and contractile dysfunction. Furthermore, this work has demonstrated that hydrogen sulfide significantly attenuates the progression of heart failure (ischemic-induced, pressure-induced, and high fat diet-induced) and improves survival following myocardial infarction. Current studies are aimed at understanding how the endogenous production of hydrogen sulfide is regulated and the determining the impact of hydrogen sulfide production on cellular signaling cascades.
Myocardial Ischemia-reperfusion injury
Myocardial ischemia-reperfusion (I/R) injury remains a leading cause of morbidity and mortality worldwide. Currently, the most effective therapeutic intervention for diminishing ischemic injury and limiting the degree of infarction is timely and effective reperfusion of the blocked artery using thrombolytic therapy or primary percutaneous coronary intervention. However, experimental and clinical investigations indicate that reperfusion salvages ischemic myocardium while further inducing cardiomyocyte death, suggesting that a cell’s fate is determined by events that occur during both periods. As such, myocardial I/R injury is a complex pathophysiological event characterized by a cascade of responses that ultimately leads to cell survival or death. We currently have several projects aimed at understanding the pathophysiology of myocardial I/R injury. Specifically, we are focusing on mitochondrial dynamics, necroptosis, and neutrophils.
Targeting LRH-1 with small molecules
Liver receptor homolog 1 (LRH-1) is a nuclear hormone receptor that acts as an important regulator of lipid and glucose metabolism. In collaboration with Ortlund Lab at Emory, we have are leveraging new insights from our crystal structures of LRH-1 bound to agonists to design and evaluate a large library of LRH-1-targeted compounds in models of high fat-induced obesity and colitis.