Role of estrogen receptor alpha in uterine epithelial-stromal interactions

描述（由申请方提供）：卵巢类固醇激素雌激素（E）和孕激素（P）的协同作用，通过其在子宫上皮和间质隔室中的同源受体起作用，决定母体的胚胎植入能力。要清楚地了解这些激素受体在生殖周期和妊娠期间调节子宫功能的分子途径，就需要定义它们在子宫中的细胞类型特异性作用。直到最近，人们才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。子宫上皮细胞ERα条件性敲除的建立揭示了E诱导的子宫上皮细胞增殖不依赖于上皮细胞ERα。这一发现导致了一种假说，即E可能通过旁分泌机制通过间质ERα控制子宫上皮增殖。为了验证这一新的模式，有必要建立一个条件性基因敲除小鼠模型，其中ERα在子宫基质细胞中特异性缺失。该R21应用的主要目的是开发Hand 2-Cre转基因小鼠，其中在Hand 2基因的11-kb调节区的控制下，Cre重组酶表达将仅在子宫基质细胞中响应于P而被诱导，从而消除这些细胞中的“floxed”ERα基因。这种小鼠模型将为ERα在妊娠建立期间指导基质-上皮对话的作用提供新的见解，并将成为子宫生物学领域研究人员的一个非常有价值的工具。

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.