PROJECT SUMMARY/ABSTRACT One in four women dies from cardiovascular disease (CVD), and living in a postmenopausal estrogen-deficient state increases susceptibility to metabolic dysfunction and CVD. The candidate’s long-term goal is to develop an independent research career as a translational endocrinologist focused on the development of novel science- based strategies for treating or preventing metabolic syndrome and associated comorbidities in menopausal women. The overall research objective for this Career Development Award (CDA-2) is to identify the effect of a novel menopause hormone therapy (a combination of conjugated estrogens and bazedoxifene (CE/BZA)) on glucose and lipid homeostasis in obese menopausal women veterans with prediabetes and early diabetes. The central hypothesis is that treatment with CE/BZA will improve beta-cell function and therefore glucose homeostasis and promote hepatic de novo lipogenesis (DNL) without promoting hepatic lipid accumulation. The rationale for the proposed research program is that its successful completion will provide important new insights regarding the use of CE/BZA to prevent or treat estrogen deficiency-induced metabolic dysfunction in obese postmenopausal women, while at the same time providing the means to establish the candidate’s early research independence as a translational scientist. Two specific aims are proposed: 1) Validate that CE/BZA improves beta cell function, and 2) identify the mechanisms of CE/BZA on hepatic DNL. The physical and intellectual research environments at Southeast Louisiana Veterans Healthcare System (SLVHCS) are supportive of professional development in the areas of sex hormones and diabetes. Three training goals are proposed: 1) Gaining expertise in prospective clinical study design and implementation, 2) obtaining proficiency in commonly used basic and translational science research techniques for assessment of glucose homeostasis and lipid metabolism, and 3) expanding the candidate’s professional portfolio, including grant proposal writing, networking, mentoring and communication skills. The proposed research is significant because in the future, with more insight into the clinical and molecular mechanisms of CE/BZA, it may be possible to prevent or treat estrogen deficiency-induced metabolic dysfunction, including obesity, hyperlipidemia, type 2 diabetes mellitus, and nonalcoholic fatty liver disease in postmenopausal women, all of which play a key role in cardiovascular complications. Findings from the proposed research are expected to position the candidate to submit a competitive VA Merit application focusing on treating or preventing metabolic syndrome and associated comorbidities in menopausal women veterans. Ultimately, results of this research continuum are expected to have an important positive impact on developing innovative therapies to decrease risk for CVD, the leading cause of death for women worldwide.

PROJECT NARRATIVE The proposed research is relevant to women veterans and public health because it focuses on developing novel and alternative strategies to treat or prevent metabolic dysfunction and associated comorbidities in postmenopausal women with prediabetes and early diabetes. Once such strategies have been established, there is the potential for momentous progress in prevention or treatment of estrogen deficiency-induced metabolic dysfunction, ultimately decreasing cardiovascular disease risk factors. Thus, the proposed research is relevant to the part of the VA's Research mission that refers to improving Veterans' health and well-being by reducing disease and disability.