Cardiovascular disease (CVD) is the foremost cause of mortality in the United States, and accounts for over $500 billion per year in economic burden. Chronic stress ranks as one of the leading biobehavioral risk factors for CVD, a relationship that is partially attributable to inflammatory processes elevated during stress. An exciting arena of scientific advancements is focusing on identifying the specific pathways through which chronic stress influences inflammatory activity with emerging evidence to suggest that sleep, which is commonly disrupted during periods of stress, may serve as one key mechanism linking stress and elevated levels of inflammation. It is critical to advance understanding of the interplay between stress and sleep in predicting levels of inflammatory activity because sleep represents a modifiable health behavior. That is, sleep can be targeted for intervention in ways that may ameliorate the deleterious effects of stress on levels of inflammation, and ultimately, CVD risk. This K08 Mentored Clinical Scientist Research Career Development Award seeks to build on my prior training and research to investigate the role of sleep as a pathway linking chronic stress and markers of inflammatory activity relevant to CVD risk. First, this award will provide the opportunity to deepen my understanding of sleep physiology, measurement, and research methodologies, as well as obtain advanced training in longitudinal statistical methods, women's health, and gene expression/immunobiology. Second, as part of an ongoing longitudinal study, I will examine the prospective associations between sleep, measured objectively using actigraphy, and measures of inflammation, including circulating inflammatory mediators (IL-6, TNF-alpha, and CRP) and monocyte expression of targeted inflammatory genes (IL6, TNF, IL1B) in chronically stressed and low stress maternal caregivers followed over 18-months to test whether sleep mediates the stress-inflammation link. This comprehensive training plan and innovative research study will help to elucidate the interdependent relationships between stress and sleep in predicting inflammatory processes key to cardiovascular health. Moreover, findings from this research will lay the foundation for the development and application of novel therapeutic strategies targeting sleep behavior to reduce levels of inflammation among individuals at elevated risk for CVD, particularly those experiencing high levels of stress. PUBLIC HEALTH RELEVANCE: The proposed study will be the first to prospectively evaluate sleep as a novel pathway through which chronic psychological stress promotes inflammation, a key mechanism in the development of cardiovascular disease. Because sleep represents a modifiable health behavior, this study holds promise for the development and application of effective, targeted sleep interventions to reduce inflammation, and ultimately cardiovascular disease risk in high stress populations. An in-depth understanding of how sleep disturbance influences cardiovascular risk, particularly among those experiencing chronic stress, is critical t our prevention and treatment of this costly disease.