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

新型雌激素对绝经后糖尿病前期女性退伍军人血糖和血脂的影响

• 批准号: 10257763
• 负责人: Dragana Lovre
• 金额: --
• 依托单位: SOUTHEAST LOUISIANA VETERANS HEALTH CARE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-10-01 至 2026-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10257763
• 关键词: Age; Applications Grants; Area; Award; Basic Science; Beta Cell; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell physiology; Clinical; Clinical Research; Clinical Trials; Communication; Conjugated Estrogens; Data; Development; Diabetes Mellitus; Disease; Effectiveness; Endocrinologist; Environment; Estrogen Therapy; Estrogens; Evolution; FDA approved; Fasting; Fatty Acids; Fatty Liver; Future; Glucose; Goals; Gonadal Steroid Hormones; Health; Healthcare Systems; Hepatic; Hepatocyte; High Risk Woman; Homeostasis; Hyperlipidemia; Hypertriglyceridemia; Innovative Therapy; K-Series Research Career Programs; Knowledge; Life Expectancy; Lipids; Louisiana; Menopausal Symptom; Menopause; Mentors; Metabolic dysfunction; Metabolic syndrome; Mission; Molecular; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oral; Personal Satisfaction; Play; Positioning Attribute; Postmenopause; Prediabetes syndrome; Predisposition; Premature Menopause; Prevention; Production; Public Health; Research; Research Design; Research Technics; Risk Factors; Science; Selective Estrogen Receptor Modulators; Serum; Time; Training; Translational Research; Triglycerides; Very low density lipoprotein; Veterans; Woman; Writing; base; blood glucose regulation; cardiovascular disorder risk; career; comorbidity; disability; effective therapy; efficacy validation; expectation; hormone therapy; human female; improved; insight; insulin secretion; islet; lipid biosynthesis; lipid metabolism; lipidomics; non-alcoholic fatty liver disease; novel; novel therapeutics; prevent; programs; prospective; skills; translational scientist

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.

项目总结/摘要 四分之一的女性死于心血管疾病（CVD），并生活在绝经后雌激素缺乏的环境中。 这种状态会增加对代谢功能障碍和CVD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的独立研究生涯，专注于新科学的发展- 治疗或预防绝经后代谢综合征和相关合并症的基础策略 妇女这项职业发展奖（CDA-2）的总体研究目标是确定 新的绝经激素疗法（结合雌激素和苯多昔芬（CE/BZA）的组合）， 糖尿病前期和早期糖尿病的肥胖绝经期女性退伍军人的血糖和血脂稳态的 中心假设是，CE/BZA治疗将改善β细胞功能，从而改善葡萄糖 体内平衡和促进肝从头脂肪生成（DNL）而不促进肝脂质积累。的 提出这项研究计划的理由是，它的成功完成将提供重要的新见解 关于使用CE/BZA预防或治疗肥胖患者雌激素缺乏诱导的代谢功能障碍 绝经后妇女，同时提供建立候选人早期研究的手段 作为一名翻译科学家的独立性。提出了两个具体目标：1）证明CE/BZA改进了 β细胞功能，和2）确定CE/BZA对肝DNL的机制。身体和智力 东南路易斯安那退伍军人医疗保健系统（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 使用基础和转化科学研究技术来评估葡萄糖稳态和血脂 新陈代谢，和3）扩大候选人的专业组合，包括赠款提案写作，网络， 指导和沟通技能。这项研究意义重大，因为在未来， 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 缺乏引起的代谢功能障碍，包括肥胖、高脂血症、2型糖尿病，以及 绝经后妇女的非酒精性脂肪肝，所有这些都在心血管疾病中起着关键作用。 并发症从拟议的研究结果预计将定位候选人提交一份 专注于治疗或预防代谢综合征及相关疾病的竞争性VA Merit应用程序 更年期退伍军人的合并症。最终，这一研究连续体的结果预计将 对开发创新疗法以降低CVD风险具有重要的积极影响， 全球女性的死亡原因。