Effect of Insulin on Estrogen Receptor Alpha Activity in Human Endometrial Cells

简介(由申请者提供)：弗兰纳里博士是一名获得董事会认证的内分泌学家，他正在从事专门研究胰岛素抵抗和生殖病理学的翻译研究。胰岛素抵抗是肥胖、多囊卵巢综合征(PCOS)和2型糖尿病(T2 DM)的基本病理。她目前的研究目标是跟踪患有胰岛素抵抗的女性，并确定她们的子宫内膜功能障碍，如子宫内膜增生和不孕，是否是胰岛素抵抗时发生的代谢异常的结果。她正在与生殖内分泌学的休·泰勒博士合作，研究胰岛素如何对子宫内膜细胞产生直接影响的潜在机制。她的长期目标是为耶鲁医学院的多学科女性健康研究项目做出贡献。在接下来的五年里，弗兰纳里博士将在休·泰勒博士和罗伯特·舍温博士的指导下，将85%的时间用于培养研究技能。她将获得更多的分子生物学经验，以应用于她的子宫内膜项目，以及提高她在临床研究的设计、实施和分析方面的知识。她将受益于耶鲁大学临床研究中心(YCCI)和女性生殖健康研究(WRHR)职业发展中心提供的教师经验、与同龄人的联系以及教学课程。弗兰纳里博士建议利用分子生物学技术研究胰岛素对人类子宫内膜细胞的影响。具体地说，她将研究胰岛素如何增强子宫内膜中雌激素作用的潜在机制。初步数据显示，胰岛素激活信号通路，改变基因转录，促进子宫内膜上皮细胞增殖。她假设胰岛素诱导雌激素受体的翻译后修饰，导致基因转录的变化。这项工作将有助于理解胰岛素在子宫内膜中作为生长因子的作用。由于肥胖症和T2 DM在美国的患病率正在上升，因此确定高胰岛素血症是否会导致子宫内膜病变，如增生症和不孕症，这一点很重要。这项研究的潜在意义包括推荐减肥或在选定的子宫内膜病变治疗中使用胰岛素增敏剂。此外，T2 DM女性的治疗模式可能会改变，以限制高剂量治疗性胰岛素的暴露。 公共卫生相关性：子宫内膜功能障碍通常发生在肥胖、多囊卵巢综合征或2型糖尿病的女性中。这些妇女的胰岛素水平很高，胰岛素可能导致不规则出血、植入失败、流产、子宫内膜增生症和子宫内膜癌。这项研究着眼于胰岛素可能影响子宫内膜组织的一种方式。

DESCRIPTION (provided by applicant): Dr. Flannery is a board-certified Endocrinologist, who is pursuing a career in translational research with a specific focus on insulin resistance and reproductive pathology. Insulin resistance is an underlying pathology in obesity, the Polycystic Ovary Syndrome (PCOS), and type 2 diabetes mellitus (T2DM). Her immediate research goal is to follow women with insulin resistance, and to determine whether their endometrial dysfunction, such as endometrial hyperplasia and infertility, is a consequence of the metabolic abnormalities occurring in insulin resistance. She is collaborating with Dr. Hugh Taylor of Reproductive Endocrinology to examine a potential mechanism for how insulin may have a direct effect on endometrial cells. Her long-term goal is to contribute to a multi-disciplinary Women's Health research program at the Yale School of Medicine. Over the next five years, Dr. Flannery will spend 85% of her time dedicated to developing research skills with mentorship from Dr. Hugh Taylor and Dr. Robert Sherwin. She will acquire more experience in molecular biology to apply to her project on the endometrium, as well as improving her knowledge in the design, conduct, and analysis of clinical research. She will benefit from the exposure to teaching faculty, association with a peer group, and didactic coursework that is provided through the Yale Center for Clinical Investigation (YCCI) and the Women's Reproductive Health Research (WRHR) Career Development Center. Dr. Flannery proposes to study the effect of insulin on human endometrial cells, using techniques in molecular biology. Specifically, she will examine a potential mechanism for how insulin may augment estrogen action in the endometrium. Preliminary data shows that insulin activates signaling pathways, alters gene transcription, and promotes cellular proliferation of endometrial epithelial cells. She hypothesizes that insulin induces a post-translational modification of the estrogen receptor, resulting in a change in gene transcription. This work will contribute to the understanding of insulin's role as a growth factor n the endometrium. Since the prevalence of obesity and T2DM is increasing in the United States, it is important to determine whether hyperinsulinemia contributes to endometrial pathology such as hyperplasia and infertility. The potential implications of this research include recommendations for weight loss or the use of insulin sensitizers in the treatment of select endometrial pathology. Also, the treatment paradigm for women with T2DM may change to limit exposure to high doses of therapeutic insulin. PUBLIC HEALTH RELEVANCE: Endometrial dysfunction commonly occurs in women with obesity, Polycystic Ovary Syndrome or Type 2 Diabetes Mellitus. These women have high levels of insulin, and insulin may contribute to irregular bleeding, implantation failure, miscarriage, endometrial hyperplasia, and endometrial carcinoma. This research looks at one way in which insulin may affect endometrial tissue.