SUMMARY The menopausal transition is a time of extensive hormonal and physiological changes for women in midlife. Unfortunately, it is often accompanied by a worsening of cardiovascular and metabolic disease risk factors, such as increases in plasma cholesterol levels, central adiposity, and blood pressure, and women have greater coronary heart disease, stroke, and mortality risk after menopause. To date, scientists only have a limited understanding of the molecular level changes that are set into motion as ovarian follicle supplies dwindle and estradiol levels fall with menopause, especially in non-reproductive tissues. We hypothesize that extensive, tissue-specific transcriptomic changes occur during and after the menopausal transition, leading to metabolic reprogramming in cardiometabolic tissues. Here, our first aim will be to use a chemically-induced, ovarian follicle depletion mouse model of the menopausal transition to identify menopause-induced changes in chromatin accessibility and gene expression in mouse liver, adipose, and aorta tissues. In addition to “menopausal” female and control-treated male and female (estrous cycling) mice, there will also be groups of “menopausal” mice implanted with estradiol versus placebo tubing. This experiment will allow comparisons between female follicle- depleted (“menopausal”) and cycling mice, between follicle-depleted mice implanted with E2 and control tubing, between female cycling mice at distinct stages of the estrous cycle (high E2 vs. low E2), and between male and female mice. Our second aim is to identify elements of women’s omics profiles associated with menopause status and time since menopause. To do this, we will compare transcriptomic, metabolomic, and proteomic profiles between premenopausal and postmenopausal women in studies with enough premenopausal and postmenopausal samples. Completion and integration of these aims will help to identify factors driving the increase in cardiovascular disease risk during the menopausal transition, their downstream targets, and the impact of estradiol hormone therapy on reversal of the changes. Clinically, this could help to optimize the timing and type of interventions that could be used in the future to control cardiovascular disease risk in midlife women.