Conversion of ERalpha cells to ERbeta cells in a cell lineage

细胞谱系中 ERalpha 细胞向 ERbeta 细胞的转化

基本信息

批准号：
9756432
负责人：
CHEMYONG JAY KO
金额：
$ 19.83万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-06 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9756432
关键词：
Cell Lineage Cells DNA Sequence Alteration Development ESR1 gene ESR2 gene Embryo Enterobacteria phage P1 Cre recombinase Epigenetic Process Epithelium Estradiol Estrogen Receptor alpha Estrogen Receptor beta Estrogen Receptors Estrogens Exposure to FOXL2 gene Gonadal Ridge Gonadal Steroid Hormones Infertility Investigation Knock-out Laboratories Lead Location Longevity Malignant neoplasm of prostate Mesonephric structure Methods Methylation Modification Molecular Mus Mutant Strains Mice Oocytes Organ Ovarian Ovary Pathologic Phenotype Physiological Primordial Follicle Receptor Gene Regulatory Element Reporter Genes Role Surface Testing Tissues Transgenic Mice Transgenic Organisms cell type design endometriosis epigenetic regulation fascinate fetal granulosa cell improved innovation malignant breast neoplasm novel outcome forecast promoter receptor reproductive function reproductive organ response theca cell toxicant

项目摘要

PROJECT SUMMARY / ABSTRACT This study aims to test the hypothesis that an ESR1-expressing cell can be converted to an ESR2-expressing cell and investigate the molecular mechanism that controls the switch. 17β−estradiol (E2) is the key sex hormone regulating development and function of reproductive organs. While two estrogen receptors, ESR1 and ESR2, are well known to be responsible for the classical actions of E2, recent investigations into the functional role of ESR2 show that E2 elicits physiological responses from ESR2-expressing cells that are often completely opposite to those from ESR1-expressing cells. Importantly, while ESR1- and ESR2-expressing cells are co-existent in most of estrogen-responsive organs or tissues, ESR1 and ESR2 are expressed in different cell types. For example, ESR1 is expressed in the surface epithelium and theca cells in the ovary, whereas ESR2 is expressed exclusively in the granulosa cells (GC). No ovarian cell expresses both receptors. We recently made an unexpected observation during a characterization of a transgenic mouse line (Esr1iCreEsr2flox/flox) in which the Esr2 gene was designed to be ablated by a Cre recombinase whose expression was regulated by the endogenous Esr1 gene promoter. In other words, in this transgenic mouse line, the Esr2 gene was deleted in the ESR1 lineage cells. Surprisingly, we found that these transgenic mice were completely deficient of ESR2 expression in the granulosa cells, which otherwise express ESR2 abundantly. This finding indicates that GC lineage cells express ESR1 for some period prior to beginning to express ESR2, evidence of a conversion of ESR1 to ESR2 in the GC lineage. In this study, we will determine exactly when the ESR1 to ESR2 conversion occurs and what underlying mechanism controls the ESR1 and ESR2 expression, using novel transgenic mouse lines that the PI's laboratory generated.

项目摘要 /摘要这项研究旨在检验以下假设，即表达ESR1的细胞可以转换为表达ESR2 细胞并研究控制开关的分子机制。 17β-雌二醇（E2）是关键性别马龙调节生殖器官的发展和功能。而两个雌激素受体，ESR1 众所周知，ESR2是E2的经典行为，最近对 ESR2的功能作用表明，E2引起了表达ESR2细胞的物理反应，这些反应通常是与表达ESR1的细胞完全相反。重要的是，虽然ESR1-和ESR2表达细胞在大多数雌激素反应器官或组织中共存，ESR1和ESR2在不同的细胞类型。例如，ESR1在卵巢的表面上皮和theca细胞中表达，而ESR2仅在颗粒细胞（GC）中表达。没有卵巢细胞表达两个受体。最近，我们在转基因小鼠系的表征中进行了意外的观察（ESR1ICREESR2FLOX/FLOX），其中ESR2基因被设计为被CRE重组酶消融表达受内源性ESR1基因启动子的调节。换句话说，在这个转基因鼠标中线，将ESR2基因删除在ESR1谱系细胞中。令人惊讶的是，我们发现这些转基因小鼠在颗粒细胞中完全定义了ESR2表达，否则表达ESR2 几乎完全是。这一发现表明GC谱系单元在开始之前表达ESR1的一段时间 Exters ESR2，表明在GC谱系中ESR1转化为ESR2的证据。在这项研究中，我们将确定究竟何时发生ESR1到ESR2转换以及基本机制控制ESR1和 ESR2表达，使用PI实验室产生的新型转基因小鼠系。