Role of estrogen receptor alpha in uterine epithelial-stromal interactions

雌激素受体α在子宫上皮-基质相互作用中的作用

基本信息

批准号：
8622699
负责人：
MILAN K BAGCHI
金额：
$ 23.79万
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：
2014
资助国家：
美国
起止时间：
2014-04-19 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8622699
关键词：
5&apos Flanking Region Adult Biological Biology Cell Proliferation Cells DNA Development Embryo Endometrial Endometrial Stromal Cell Endometrium Epithelial Epithelial Cells Epithelial-Stromal Communication Epithelium Estrogen Receptor alpha Estrogen Receptors Estrogens Event Excision Female Fertility Functional disorder Generations Genes Germ Lines Growth Health Hormone Receptor Hormones Infertility Knock-out Knockout Mice Laboratories Link Mediating Methodology Modeling Molecular Mus Neonatal Nucleic Acid Regulatory Sequences Ovarian Steroid Hormone Pathway interactions Pattern Pregnancy Process Progesterone Progesterone Receptors Regulatory Element Research Personnel Role Series Signal Transduction Steroid Receptors Steroids Stromal Cells Testing Tissue Recombination Tissues Transgenic Mice Uterus Validation base cell type implantation insight mouse genome mouse model mutant mouse model natural Blastocyst Implantation novel paracrine preimplantation promoter receptor recombinase reproductive response tool transcription factor transmission process

项目摘要

DESCRIPTION (provided by applicant): Concerted actions of the ovarian steroid hormones estrogen (E) and progesterone (P), acting via their cognate receptors in uterine epithelial and stromal compartments, determine the maternal competency for embryo implantation. A clear understanding of the molecular pathways via which these hormone receptors regulate uterine functions during the reproductive cycle and pregnancy would require a definition of their cell type-specific roles in the uterus. Until recently, it was thought that estrogen receptor alpha (ERα present in the epithelial cells drives the E-induced proliferation of these cells during the reproductive cycle. Generation of a conditional knockout of ERα in uterine epithelium has revealed the surprising fact that E-induced proliferation of uterine epithelial cells is independen of the epithelial ERα. This finding has led to the hypothesis that E may act via the stromal ERα to control uterine epithelial proliferation by paracrine mechanisms. To test this new paradigm, it is necessary to create a conditional knockout mouse model in which ERα is deleted specifically in the uterine stromal cells. A major objective of this R21 application is to develop the Hand2-Cre transgenic mice in which Cre recombinase expression, under the control of an 11-kb regulatory region of the Hand2 gene, will be induced exclusively in the uterine stromal cells in response to P, thereby ablating the "floxed" ERα gene in these cells. This mouse model will provide novel insights into the role of ERα in directing stromal-epithelial dialogue during the establishment of pregnancy and would serve as an extremely valuable tool for researchers in the field of uterine biology.

描述（由申请人提供）：卵巢类固醇激素雌激素（E）和黄体酮（P）通过子宫上皮和间质室中的同源受体发挥协同作用，决定母体胚胎植入的能力。通过这些激素受体在生殖周期和怀孕期间调节子宫功能的途径，需要定义它们在子宫中的细胞类型特异性作用。认为上皮细胞中存在的雌激素受体α（ERα）在生殖周期中驱动E诱导的这些细胞的增殖。在子宫上皮中条件性敲除ERα的产生揭示了一个令人惊讶的事实，即E诱导的子宫上皮细胞增殖这一发现导致了这样的假设：E 可能通过间质 ERα 通过旁分泌机制控制子宫上皮增殖。为了测试这一新范例，有必要创建一个条件性敲除小鼠模型，其中 ERα 在子宫基质细胞中被特异性删除。该 R21 应用的一个主要目标是开发 Hand2-Cre 转基因小鼠，其中 Cre 重组酶在其中表达。 Hand2 基因的 11-kb 调控区的控制将专门在子宫基质细胞中诱导响应 P，从而消除这些细胞中的“floxed”ERα 基因该小鼠模型将为了解 ERα 在妊娠建立过程中指导基质-上皮对话的作用提供新的见解，并将为子宫生物学领域的研究人员提供极其有价值的工具。