This career development award will support Dr. Karen Ryan s continued training in the field of MetabolicDiseases, focusing on cardiovascular physiology and stress neurobiology, and will facilitate her transition toindependence. Her long-term career goal is to be an independent academic researcher in the field of systemsneuroendocrinology, with a focus on elucidating specific mechanisms linking environmental signals with thedevelopment of metabolic syndrome and cardiovascular dysfunction. Recent evidence supports depression,anxiety, and chronic stress as contributing risk factors for cardiovascular disease (CVD). This is anunderstudied but critical area of research, since CVD remains the leading cause of mortality in the US. Inaddition to chronic psychological conditions, exaggerated physiological reactions to acute stressors have alsobeen linked to poor cardiovascular outcomes. However the specific mechanisms linking psychological stressto CVD remain unexplained, despite significant implications for understanding and treating CVD. Preliminarydata demonstrate that signaling by the lipid-activated nuclear receptor, PPAR potently abrogated bothcardiovascular and HPA responses to acute psychological stress in rats. Moreover, PPAR signaling bluntedearly neuronal activation in the paraventricular nucleus of the hypothalamus (PVH). Although PPAR isexpressed in the PVH and other brain regions critical to the cardiovascular and hormonal responses to stress,and although PPAR signaling is associated with improvements in indices of CVD in both rats and in humans,virtually nothing is known about the role of brain PPAR in the integrated stress response or in chronic stress-induced cardiovascular dysfunction. This proposal will test the overall hypothesis that CNS PPAR signaling isan integral part of the physiological stress response, and plays a major role to blunt cardiovascular andendocrine pathologies engendered by prolonged stress. I plan to test the overall hypothesis by pursuing threespecific aims. SA1 is to test the hypothesis that activation of PPAR , by pharmacological agonists and/orendogenous lipid agonists, blunts cardiovascular and HPA responses to acute stress. SA2 is to test thehypothesis that activation of PPAR blunts the adverse systemic and cardiovascular responses to chronicvariable stress (CVS).
These aims, to be completed during the mentored phase, will facilitate training in newtechniques. Career development activities include academic and grant-writing course-work, as well as regularmeetings with the Career Advisory Committee (CAC). SA3 is to test the hypothesis that CNS PPAR signalingis sufficient to blunt acute responses to stress, and the adverse systemic and cardiovascular responses toCVS.
This aim builds on Dr. Ryan s postdoctoral work on the brain PPAR system, and on the training she willreceive during the mentored phase. The CAC will remain active mentors, a role that includes providingconstructive critiques of Dr. Ryan s first R01 submission.
Cardiovascular disease (CVD) is the leading cause of death among men and women in the United States.Both heightened reactions to acute psychological stress and chronic exposure to stressful situations areassociated with increased risk for CVD. This proposal seeks to understand the mechanisms linkingpsychological stress to CVD; and the role for the lipid-activated receptor PPAR? in this process.
