Understanding Progesterone Receptor action in Obesity for Endometrial Cancer Prevention

了解孕酮受体在肥胖中的作用以预防子宫内膜癌

基本信息

批准号：
10680493
负责人：
Ji-Yong Julie Kim
金额：
$ 62.75万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
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：
2019-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10680493
关键词：
3-Dimensional Adipocytes Adipose tissue Affect Benign Biological Models Cell Count Cells ChIP-seq Coculture Techniques DNA Methylation Development Diagnosis Disease Endometrial Endometrial Carcinoma Endometrial Neoplasms Endometrial adenocarcinoma Endometrium Environment Epigenetic Process Epithelial Cells Estrogens FOXO1A gene Fostering Gene Expression Genes Genomics Goals Growth Histones Hormones Human In Vitro Incidence Malignant Female Reproductive System Neoplasm Malignant Neoplasms Menstrual cycle Metformin Microfluidics Modernization Molecular Obesity Organ Organoids Pathway interactions Patients Phenotype Premenopause Process Progesterone Progesterone Receptors Proto-Oncogene Proteins c-akt Public Health Research Resistance Risk Risk Factors Role Sample Size Signal Transduction Stromal Cells System Technology Testing Time Tissues Woman Work bisulfite sequencing carcinogenesis deep sequencing endometrial cancer prevention endometrial organoid epigenome genome-wide analysis high risk high risk population in vitro Model inhibitor innovative technologies insight microfluidic technology obese person permissiveness prevent protective effect receptor release factor response single-cell RNA sequencing theories transcriptome tumor tumorigenesis tumorigenic whole genome

项目摘要

The incidence of endometrial cancer is on the rise each year reaching over 60,000 new cases in the US in 2018. Obesity remains a significant public health problem and is a major risk factor for developing endometrial cancer. Although excess estrogen from adipose tissues is thought to predispose a woman from developing endometrial cancer, the protective role of progesterone in obesity is unknown. Studies demonstrate that the excess estrogen theory in obese women does not always hold true particularly in the premenopausal state. We hypothesize that adipose tissue release factors that activate the AKT pathway in endometrial epithelial cells to blunt progesterone receptor (PR) action, thereby increasing the risk of endometrial neoplasia. In this study, we will decipher the actions of PR in the human endometrium in the presence or absence of adipocytes using 3D spheroid cultures in microfluidic systems. These innovative technologies allow us to study for the first time, the effect of adipocytes on the signaling and genomic activities that affect progesterone sensitivity. We will determine how adipocytes affect progesterone driven differentiation and survival of the endometrial organoids and how changes in epigenetics, including DNA methylation and histone marks, affect the ER and PR cistrome. Unbiased sequencing will be done using technologies that allow for deep sequencing of small cell numbers. This research will generate insight into the early changes that may lead to tumorigenesis which will be useful to determine how to effectively prevent endometrial cancer in the obese women who are at high risk.

子宫内膜癌的发病率逐年上升，2018 年美国新增病例超过 60,000 例。肥胖仍然是一个重大的公共卫生问题，也是发生子宫内膜癌的主要危险因素。尽管脂肪组织中过量的雌激素被认为会使女性容易患子宫内膜癌，但黄体酮在肥胖中的保护作用尚不清楚。研究表明，肥胖女性体内雌激素过多的理论并不总是成立，尤其是在绝经前状态。我们假设脂肪组织释放激活子宫内膜上皮细胞中 AKT 通路的因子，从而减弱孕酮受体 (PR) 的作用，从而增加子宫内膜肿瘤的风险。在这项研究中，我们将使用微流体系统中的 3D 球体培养物来解读 PR 在存在或不存在脂肪细胞的情况下在人类子宫内膜中的作用。这些创新技术使我们首次研究脂肪细胞对影响黄体酮敏感性的信号传导和基因组活动的影响。我们将确定脂肪细胞如何影响孕酮驱动的子宫内膜类器官的分化和存活，以及表观遗传学的变化（包括 DNA 甲基化和组蛋白标记）如何影响 ER 和 PR 顺反组。无偏测序将使用允许对小细胞数量进行深度测序的技术来完成。这项研究将深入了解可能导致肿瘤发生的早期变化，这将有助于确定如何有效预防高危肥胖女性的子宫内膜癌。