Cardiac Regeneration. While cardiac regeneration was once thought to be limited to organisms such newts and zebrafish, recent studies have demonstrated that mammals also have some regenerative capacity. We are combining genomic and high-throughput microscopy experiments with computational models to map the molecular networks and identify compounds that stimulate cardiac myocyte proliferation.
Cardiac inflammation and extracellular matrix remodeling. Cardiac macrophages and fibroblasts play important roles in inflammation and wound healing following cardiac injury. Yet systems and therapeutic approaches targeting these cells have been limited. We are collaborating with investigators at UVA and externally to reconstruct the molecular networks in fibroblasts and macrophages in the context of myocardial infarction.
Cardiac hypertrophy. Dozens of pathways are implicated in cardiac myocyte growth, but little is known about the quantitative contribution of these pathways to myocyte shape, reversibility, sarcomeric organization, or many other factors affecting the progression of heart failure. We are combining high-throughput microscopy, automated image processing, and large-scale network modeling to address these challenges.
β-adrenergic signaling and beta blockers in heart failure. Do beta blockers work by suppressing or resensitizing the β-adrenergic pathway? Would patients with receptor polymorphisms benefit from personalized therapies? We are coupling integrated models of signaling and contractile function with video microscopy of Ca2+ dynamics.
cAMP/PKA compartmentation. cAMP and PKA are central hubs transmitting signals from dozens of receptors to hundreds of effectors. We are studying how compartmentation (subcellular localization) of cAMP and PKA determines the input/output specificity of the network. Key methods are imaging genetically-encoded FRET biosensors and computational models with realistic cellular geometries. Dysregulated cAMP compartmentation is a key element of heart failure.
Funding: National Institutes of Health, National Science Foundation, American Heart Association, AstraZeneca, Coulter Foundation, University of Virginia