PROJECT SUMMARY/ABSTRACT The present project is part of the Centers of Biomedical Research Excellence (COBRE) grant focused on research on redox biology mechanisms of cardiovascular disease. The objective of the COBRE Center for Redox Biology and Cardiovascular Disease is to establish a nationally recognized research and training program that develops federally funded junior faculty research while revealing new insights into cardiovascular pathology. One of the major goals of this COBRE program is to advance mechanistic understanding of redox biology regulation in cardiovascular pathophysiology. To accomplish this goal, the COBRE program provides a consistent and robust mentorship and professional development program, funding, and core facility support to junior faculty projects investigating the redox biology mechanisms of cardiovascular disease that will be competitive for independent federal funding. The proposed research is part of a current, funded COBRE pilot project focused on investigating the sex-specific effects of redox imbalances on the heart. The main goal of this proposed supplement is to expand our current studies on sexual dimorphism. We aim to elucidate, for the first time, the direct effects of confinement-induced mental stress on the female heart, and to test whether increased mental stress leads to alterations in critical genes involved in antioxidant pathways in the heart. Since we are facing an unprecedented situation involving social distancing and confinement with the COVID-19 pandemic, understanding the long-term cardiac effects of mental stress triggered by confinement is currently of great interest. Women are at high risk of developing cardiac events in response to mental stress. Stress levels in women have been shown to correlate with delayed recovery, recurrence, and increased mortality after a heart attack compared with age-matched men. However, the mechanisms underlying these sex differences are not precise. In this proposal, we plan to evaluate the direct and long-term effects of confinement stress on the female heart, and to test whether exposure to this stressor leads to adverse outcomes in females by altering the expression of genes involved in maintaining the redox balance in cardiomyocytes. Our preliminary data revealed that confinement stress induces sex-specific changes in the expression of cyclin-dependent kinase inhibitor 1A (Cdkn1A), which activates the master regulator of the intracellular antioxidant response, nuclear factor erythroid- 2-related factor 2 (Nrf2). With the support of this supplement, if awarded, we will test if Cdkn1A in the female heart is under the direct regulation of the glucocorticoid receptor (GR), the stress hormone receptor. Also, we will test whether changes in the levels of Cdkn1A have effects on Nrf2 downstream signaling in the heart that may predispose females to heart disease and its complications. The results gathered in this proposal will provide the basis for future studie...