Stress-induced immune reprogramming in cardiovascular disease

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PROJECT SUMMARY Psychosocial stress is a critical risk factor for cardiovascular disease. However, current cardiovascular risk management strategies include few evidence-based interventions to address psychosocial stress’s detrimental effects on this disease. With the current global events, notably the ongoing COVID-19 pandemic and the increasing burden of atherosclerotic heart disease, modulating stress’ effects is warranted. The goal of our current proposal is mechanistically understanding psychosocial stress’s impact on the immune system and inflammatory atherosclerosis to lower residual cardiovascular risk in patients. Over the course of our Type-1 Program, we substantially contributed to knowledge about the links between psychosocial stress and cardiovascular disease by identifying tissular, cellular, and molecular pathways that connect nervous, immune, and vascular systems. Specifically, we found that stress perception mechanisms influence atherosclerosis development and regression. We developed sophisticated tools to study specific brain regions and their contributions to stress perception. We made substantial progress on translational imaging studies in atherosclerosis. In clinical studies, we are gaining ground on understanding the neuro-immune-arterial pathway. Our collaborative efforts to studying how stress affects the immune system have yielded new, innovative research questions we are now eager to explore. Drawing on our Type-1 Program, in the current proposal, we will not merely investigate macrophage biology; we will broaden our scope to acquire a complete picture of immune reprogramming in psychosocial stress-aggravated atherosclerotic disease. Our Program’s broader perspective includes more expansively evaluating different brain circuits and employing a wide variety of imaging methods while pursuing more in-depth analyses (omics) and optimal data integration. This innovative approach will elevate our understanding of the complex interrelation between stress perception and cardiovascular immunology, simultaneously extending the Program’s clinical scope. We will approach this highly innovative program with our multidisciplinary team including the previous program’s principal investigators, most of its key investigators, as well as new collaborators in neuroscience, psychiatry, and trained immunity. Our program will yield critical insights into how stress- induced immune reprogramming exacerbates (ongoing) cardiovascular disease. Its successful completion will not only lay the foundation for unique (i) scientific insights into immune mechanisms that are regulated neurologically and drive cardiovascular disease development but also yield (ii) a forward-thinking approach to managing cardiovascular disease in individuals experiencing prolonged episodes of psychosocial stress and identify novel (iii) therapeutic targets and treatments.