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

胰岛素对人子宫内膜细胞雌激素受体α活性的影响

• 批准号: 8384143
• 负责人: Clare Ann Flannery
• 金额: $ 13.17万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-21 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8384143
• 关键词: Affect; Beta Cell; Binding; Body Weight decreased; Cell Proliferation; Cells; Chemosensitization; Clinical Research; Clinical Trials; Data; Dose; Educational process of instructing; Endocrinologist; Endometrial; Endometrial Carcinoma; Endometrial Hyperplasia; Endometrium; Epithelial Cells; Estradiol; Estrogen Receptor alpha; Estrogen Receptors; Estrogens; Exposure to; Faculty; Functional disorder; Genetic Transcription; Goals; Growth Factor; Hemorrhage; Human; Hyperinsulinism; Hyperplasia; Infertility; Insulin; Insulin Receptor; Insulin Resistance; Insulin Signaling Pathway; Knowledge; Ligands; MAP Kinase Gene; Mediating; Mentorship; Metabolic; Molecular Biology; NCOA3 gene; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Obesity; PI3K/AKT; Pathology; Pathway interactions; Peer Group; Phosphorylation; Phosphotransferases; Polycystic Ovary Syndrome; Post-Translational Protein Processing; Prevalence; Proto-Oncogene Proteins c-akt; Recommendation; Relative (related person); Reproductive Endocrinology; Reproductive Health; Research; Response Elements; Role; Serine; Signal Pathway; Spontaneous abortion; Techniques; Therapeutic; Time; Tissues; Translational Research; United States; Woman; Women' s Health; Work; career; career development; design; experience; failure Implantation; human FRAP1 protein; improved; insulin sensitizing drugs; insulin signaling; medical schools; programs; reproductive; skills

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.

描述（由申请人提供）：Flannery博士是一位经过董事会认证的内分泌学家，他正在从事转化研究职业，特别关注胰岛素抵抗和生殖病理学。胰岛素抵抗是肥胖症，多囊卵巢综合征（PCOS）和2型糖尿病（T2DM）的一种潜在病理。她的直接研究目标是跟随具有胰岛素抵抗的女性，并确定其子宫内膜功能障碍（例如子宫内膜增生和不育）是否是胰岛素抵抗中发生代谢异常的结果。她正在与生殖内分泌学的休·泰勒（Hugh Taylor）博士合作，以研究胰岛素如何直接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大学医学院的多学科女性健康研究计划做出贡献。在接下来的五年中，弗兰纳里（Flannery）博士将花费85％的时间，致力于通过休·泰勒（Hugh Taylor）博士和罗伯特·舍温（Robert Sherwin）博士的指导来发展研究技能。她将获得更多关于分子生物学的经验，以应用于子宫内膜项目，并提高她对临床研究的设计，行为和分析的知识。她将受益于通过耶鲁大学临床调查中心（YCCI）和妇女生殖健康研究中心（WRHR）职业发展中心提供的教学教师，与同伴团体的联系以及教学课程。 Flannery博士建议使用分子生物学中的技术研究胰岛素对人子宫内膜细胞的影响。具体而言，她将研究一种潜在的机制，即胰岛素如何增加子宫内膜中的雌激素作用。初步数据表明，胰岛素激活信号通路，改变基因转录，并​​促进子宫内膜上皮细胞的细胞增殖。她假设胰岛素诱导雌激素受体的翻译后修饰，从而导致基因转录的变化。这项工作将有助于理解胰岛素作为子宫内膜生长因子的作用。由于美国肥胖和T2DM的患病率正在增加，因此确定高胰岛素血症是否有助于子宫内膜病理（例如增生和不育）很重要。这项研究的潜在影响包括减肥或使用胰岛素敏化剂在某些子宫内膜病理学治疗中的建议。同样，针对T2DM女性的治疗范例可能会改变以限制暴露于高剂量的治疗性胰岛素。 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。这些妇女具有高水平的胰岛素，胰岛素可能导致出血，植入衰竭，流产，子宫内膜增生和子宫内膜癌的不规则出血。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。