The Role of Mitochondrial DNA in Innate Immune Activation after Sudden CardiacArrest

摘要

ABSTRACT Sudden cardiac arrest is highly prevalent among hospitalized veterans and results in overwhelming mortality. Unfortunately, there are no pharmacologic therapies that have been shown to reliably increase survival after sudden cardiac arrest. Survivors of sudden cardiac arrest typically have systemic organ damage requiring intensive care in the hospital. The majority of these patients have reduced cardiac function and one quarter of these patients die from cardiogenic shock. Cardiac inflammation is thought to contribute to this dysfunction and is likely driven by damage associated molecular patterns (DAMPs). One prominent DAMP is mitochondrial DNA (mtDNA). Preliminary work in our lab has shown that strategies aimed at preserving mtDNA integrity, including overexpression of mitochondrial transcription factor A (TFAM), are protective to cardiac function in a mouse model of sudden cardiac arrest. TFAM is a nuclear gene that regulates mtDNA expression, packaging, and copy number and is known to be protective in a number of heart disease models. My overarching hypothesis is that ischemia-reperfusion injury from cardiac arrest results in mtDNA release, which triggers an inflammatory response in the heart, and that this response is dependent upon cGAS/STING signaling. To explore this hypothesis, I will pursue three specific aims. In Aim 1, I will explore the mechanism by which mtDNA is released using microscopy in vitro and confirm these changes in an in vivo model of sudden cardiac arrest. In Aim 2, I will use transgenic mouse models to manipulate TFAM to affect mtDNA release and also knock-out STING signaling to explore the relationship between mtDNA release and inflammation after sudden cardiac arrest. In Aim 3, I will characterize the inflammatory response in the heart after sudden cardiac arrest and manipulate cGAS/STING signaling to evaluate cGAS/STING mediated inflammatory changes. Together, these aims will evaluate the role of mtDNA release following sudden cardiac arrest and its role in innate immune signaling, which may guide future therapies for human studies. This work will support my goal of transitioning into an independent research career as a physician-scientist studying mitochondrial changes in cardiovascular disease. This grant will support continued research and career development at both the Veterans Administration Hospital in Pittsburgh and the University of Pittsburgh, including coursework, career mentorship, and scientific training aimed at transitioning to independence as a physician scientist in the Veterans Administration system.