Current Areas of Investigation
CARDIOPROTECTIVE STRESS SENSING AND SIGNALING
BY OXIDIZED PROTEIN KINASE A (PKA)
Reactive oxygen and nitrogen species (ROS and NO, respectively) regulate diverse sets of physiological processes across all forms of life, but we don’t often think of the oxidase enzymes that produce them as adaptive stress sensors. Yet, a growing number of studies show stimulated ROS/NO production is both crucial for ensuring functional plasticity during eustress and required for cell adaptation and survival under pathological perturbations. Stable, yet reversible, redox regulation of signaling biomolecules (i.e., kinases, transcription factors) is an ideal mechanism to achieve widespread cytoprotection, although to-date only a limited number of these signaling networks have been identified. This project seeks to shed light on this underexplored concept in biology, with the long-term goal of therapeutically leveraging the critical and conserved redox signaling networks we identify to aid human health and longevity. We’re particularly focused on the recent discovery that signaling via one of the cell’s master kinases, PKA, can be redox regulated, with stress-induced oxidation of PKA leading to pronounced changes in intracellular calcium communication and improved cell adaptation and survival following ischemia.
What the lab is now focused on is understanding:
How, mechanistically, oxidation of PKA alters calcium communication to support cell adaptation and survival
Whether this adaptive mechanism is present or important in other disease settings where an altered redox state is central to the pathology (e.g., heart failure, stroke, cardiometabolic disease)
What translation potential this cardioprotective response might hold for mitigating ischemic injury and improving clinical outcomes in patients.
THE LYSOSOME AS A COMMUNICATION HUB FOR
LIFE VS. DEATH CELL DECISIONS
9.3M Americans suffer the burden of myocardial infarction (MI) each year, and for those that don’t succumb to immediate death, MI predisposes the heart to progressive functional decline and development of heart failure (HF). Gross organelle dysfunction is implicated as a causal driver of HF after MI, with defects in the sarcoplasmic reticulum (SR), mitochondria, lysosome and autophagosome all collectively contributing to cardiomyocyte death and contractile deficiencies underlying progressive decompensation. Recent evidence suggests that these seemingly autonomous pathological events may be linked via deranged inter-organelle communication. Our ongoing studies highlight an unexpected role for the lysosome to act as an amplifier of SR, mitochondrial and autophagosome-related dysfunction in the post-ischemic heart, with evidence that excessive calcium release from lysosomal two-pore channels (TPCs) contributes directly to cardiomyocyte death and deterioration. The overarching goal of this research project is to define how TPC2-dependent calcium signaling impacts on cardiac function following MI and therapeutically test if TPC2-selective inhibition can prevent HF development.