Obesity-driven endometrial hyperplasia in postmenopausal women: Synergistic role for insulin and estrone

绝经后妇女肥胖导致的子宫内膜增生：胰岛素和雌酮的协同作用

基本信息

批准号：
10593167
负责人：
Clare Ann Flannery
金额：
$ 42.04万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10593167
关键词：
Age Architecture Atypical Endometrial Hyperplasias Benign Body Weight decreased Body mass index Breast Cancer Treatment Case/Control Studies Chronic Clinical Management Data Development Diabetes Mellitus Endometrial Endometrial Carcinoma Endometrial Hyperplasia Endometrial adenocarcinoma Endometrium Enrollment Estradiol Estrogen Receptor alpha Estrogen Receptor beta Estrogen Receptors Estrogens Estrone Frequencies GPER gene Gene Expression Gene Expression Profile Genomics Gland Growth Growth Factor Histologic Histology Hormones Human Hyperinsulinism Hyperplasia Inflammation Insulin Insulin Receptor Insulin Signaling Pathway Knock-out Lesion Ligands Malignant Neoplasms Measures Mediating Menopause Metabolic Metabolic hormone Modeling Morbid Obesity Mus Non-Insulin-Dependent Diabetes Mellitus Nuclear Atypia Obesity Obesity Epidemic Outcome Ovarian Ovary Overweight Pathway interactions Pattern Pharmaceutical Preparations Placebos Postmenopause Precancerous Conditions Predisposition Prevention Process Production Progesterone Progestins Proliferating Protein Isoforms Receptor Signaling Regulation Relative Risks Reporting Research Risk Factors Role Severities Stimulation of Cell Proliferation Testing Thinness Time Tissue-Specific Gene Expression Tissues Transgenic Organisms Uterus Wild Type Mouse Withdrawal Woman Work aged clinical phenotype epidemiology study genetic signature high risk insulin signaling mouse model obesity development receptor synergism timeline transcriptome

项目摘要

PROJECT SUMMARY / ABSTRACT Obesity-driven cancers are well described, and the highest risk is reported for endometrial cancer. Epidemiological studies show an impressive escalation in endometrial adenocarcinoma (EC) as obesity severity increases, with relative risks of 1.5, 2.5, 4.5 and 7.1 for overweight, moderate, severe and very severe obesity, respectively. Rates of EC are rising with the obesity epidemic. EC has a precursor lesion, atypical endometrial hyperplasia (AEH). While AEH has a high transformation rate of 30% to EC, AEH grows slowly, offering the opportunity for prevention. However, we do not know why obesity promotes the development of AEH and EC. This project proposes to investigate two pathways for the development of obesity-driven endometrial hyperplasia in post-menopausal women. We hypothesize that pathophysiological levels of estrone promote irregular gland architecture, whereas hyperinsulinemia promotes nuclear atypia in a synergistic process that leads to atypical endometrial hyperplasia. In this project we will characterize changes in endometrial histology and uterine gene expression that occur over time, in mice who have pathophysiological levels of insulin and estrone, as occur in women with obesity. For confirmatory testing of hormone induced histology, we will use established mouse models of estrogen receptor-α (ERα) and insulin receptor (IR) deletions. We will also examine the histological effect of combined insulin and estrone stimulation in mice. Outcomes include a timeline assessment of histological and gene expression changes toward AEH. Finally, we propose a case- control study to elucidate whether insulin and estrone play a role in AEH development in post-menopausal women. We intend to enroll 30 women with AEH and 30 women without AEH, who have severe obesity. Circulating estrone and insulin levels will be measured, and endometrial tissue will be assessed for IR and ERα expression levels as well as global gene expression. We will identify insulin and estrone patterns of gene expression in AEH by comparing differential gene expression between AEH and benign endometrium to differential gene expression of uteri from insulin &/or estrone exposed mice relative to their controls. The immediate implications of this research may include opening the clinical management of AEH to the well- established strategy of weight loss, insulin-lowering agents as used in the treatment of type 2 diabetes, and estrone lowering agents as used in the treatment of breast cancer. The longer-term, broader implications of this research are to understand the mechanisms for how obesity induced metabolic and hormone changes alter susceptibility to many obesity-driven cancers.

项目概要/摘要肥胖引起的癌症已有详细描述，据报道子宫内膜癌的风险最高。流行病学研究表明，随着肥胖严重程度的增加，子宫内膜腺癌 (EC) 的发病率显着上升增加，超重、中度、重度和极重度肥胖的相对风险分别为 1.5、2.5、4.5 和 7.1， EC 的发生率随着肥胖的流行而上升，EC 具有先兆病变，即非典型子宫内膜。增生 (AEH) 虽然 AEH 向 EC 的转化率高达 30%，但 AEH 生长缓慢，提供了然而，我们不知道为什么肥胖会促进 AEH 和 EC 的发生。该项目旨在研究肥胖驱动的子宫内膜发育的两种途径我们勇敢地承认雌酮的病理生理水平会促进绝经后女性的增生。不规则的腺体结构，而高胰岛素血症在协同过程中促进核异型性，导致非典型子宫内膜增生在这个项目中，我们将描述子宫内膜组织学的变化。以及随着时间的推移，在具有病理生理水平的胰岛素和子宫基因的小鼠中发生的子宫基因表达雌酮，如肥胖女性中出现的那样，为了激素诱导的组织学的验证性测试，我们将使用我们还将建立雌激素受体-α (ERα) 和胰岛素受体 (IR) 缺失的小鼠模型。检查联合胰岛素和雌酮刺激对小鼠的组织学影响，结果包括：最后，我们提出了一个案例——AEH 的组织学和基因表达变化的时间线评估。阐明胰岛素和雌酮是否在绝经后 AEH 发展中发挥作用的对照研究我们打算招募 30 名患有 AEH 的女性和 30 名没有 AEH 且患有严重肥胖的女性。将测量循环雌酮和胰岛素水平，并评估子宫内膜组织的 IR 和 ERα 我们将确定基因的胰岛素和雌激素模式。通过比较 AEH 和良性子宫内膜之间的差异基因表达相对于对照组，胰岛素和/或雌酮暴露小鼠子宫的差异基因表达。这项研究的直接影响可能包括向健康人群开放 AEH 的临床管理。制定了减肥策略、用于治疗 2 型糖尿病的降胰岛素药物，以及用于乳腺癌治疗的雌酮降低剂具有更长期、更广泛的影响。研究目的是了解肥胖引起的代谢和激素变化如何改变的机制易患许多由肥胖引起的癌症。