Effects of Novel Estrogens on Glucose and Lipids in Postmenopausal Prediabetic Women Veterans

项目摘要/摘要 四分之一的女性死于心血管疾病，生活在绝经后雌激素缺乏的状态 国家增加了代谢功能障碍和心血管疾病的易感性。候选人的长期目标是发展 作为一名翻译内分泌学家，他的独立研究生涯专注于新科学的发展- 基于治疗或预防更年期代谢综合征及相关并发症的策略 女人。这项职业发展奖(CDA-2)的总体研究目标是确定 新的更年期激素疗法(结合雌激素和巴多昔芬(CE/BZA)) 患有糖尿病前期和早期糖尿病的肥胖绝经女性退伍军人的血糖和血脂稳态。这个 中心假设是CE/BZA治疗将改善β细胞功能，从而改善血糖 动态平衡和促进肝脏新生脂肪生成(DNL)，而不促进肝脏脂肪堆积。这个 拟议的研究计划的基本原理是，它的成功完成将提供重要的新见解 关于使用CE/BZA预防或治疗雌激素缺乏性肥胖患者的代谢功能障碍 绝经后妇女，同时提供手段，建立候选人的早期研究 作为一名翻译科学家的独立性。提出了两个具体目标：1)验证CE/BZA改进 2)明确CE/BZA对肝脏DNL的作用机制。身体上和智力上 路易斯安那州东南部退伍军人医疗系统(SLVHCS)的研究环境支持 性激素和糖尿病领域的专业发展。提出了三个培训目标：1) 获得前瞻性临床研究设计和实施方面的专业知识，2)熟练掌握 使用基础科学和翻译科学研究技术评估葡萄糖稳态和血脂 新陈代谢，以及3)扩大候选人的专业投资组合，包括拨款提案撰写、网络、 指导和沟通技巧。这项拟议的研究意义重大，因为在未来，随着更多 深入了解CE/BZA的临床和分子机制，有可能预防或治疗雌激素 缺乏导致的代谢功能障碍，包括肥胖、高脂血症、2型糖尿病和 绝经后妇女中的非酒精性脂肪性肝病，所有这些疾病在心血管疾病中都起着关键作用 并发症。预计拟议研究的结果将使候选人提交一份 竞争性VA优点应用，专注于治疗或预防代谢综合征和相关 更年期女性退伍军人的合并症。最终，这一研究连续体的结果有望 对开发创新疗法以降低心血管疾病风险产生重要积极影响 世界各地女性的死因。

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.