Role of estrogen receptor alpha in uterine epithelial-stromal interactions

描述(由申请人提供)：卵巢类固醇激素雌激素(E)和孕酮(P)通过其在子宫上皮和间质中的同源受体共同作用，决定了母亲是否有能力植入胚胎。要清楚地了解这些激素受体在生殖周期和怀孕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定角色。直到最近，人们认为雌激素受体α(ERα)存在于上皮细胞中，在生殖周期中驱动E诱导的这些细胞的增殖。在子宫上皮细胞中产生条件敲除的ERα揭示了一个令人惊讶的事实，即E诱导的子宫上皮细胞的增殖独立于上皮ERα。这一发现导致了一种假说，即E可能通过间质ERα通过旁分泌机制控制子宫上皮的增殖。为了测试这一新的范例，有必要建立一个条件基因敲除小鼠模型，在该模型中，ERα在子宫基质细胞中被特异性地删除。此R21应用的一个主要目标是发展Hand2-Cre转基因小鼠，在该转基因小鼠中，在Hand2基因的11kb调节区的控制下，Cre重组酶的表达将在子宫基质细胞中特异性地诱导，以响应P，从而去除这些细胞中的“FLOXED”ERα基因。这一小鼠模型将为ERα在妊娠形成过程中引导基质-上皮对话的作用提供新的见解，并将成为子宫生物学领域的研究人员极其宝贵的工具。

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.