The role of SMAD1 and SMAD5 in hormonal response, endometrial receptivity and glandular function

项目摘要 尽管妇女早孕流产的发生率很高，但其原因尚不清楚，而且 治疗选择有限。子宫内膜是胚胎和子宫的第一个接触部位。 因此，母亲了解胚胎时期子宫内膜的分子特征 植入将帮助我们开发预防女性早期妊娠丢失的治疗方法。骨 由骨形态发生蛋白1型受体和2型受体复合体组成的异二聚体受体复合体。之后 Smad4，并转位到细胞核以控制基因的表达。我们最近展示了信号 TGFb家族的组成成分(ALK3、ALK5、BMP7和卵泡抑素)通过以下方式对子宫内膜容受性起关键作用 控制子宫内膜对类固醇激素、雌激素(E2)和孕酮(P4)的反应。然而， TGFb途径与子宫内膜对类固醇激素的反应之间的联系机制不是 明白了。该提案的目标是确定下行信令组件如何 胚胎着床过程中的子宫内膜。我们将使用转基因小鼠和人类子宫内膜 完整描述Smad1和Smad5如何控制子宫内膜对E2和P4的反应 早孕。该奖项将支持博士后戴安娜·蒙西韦斯博士的职业发展 贝勒医学院副研究员和IRACDA研究员。候选人将由马丁博士共同指导 马祖克，斯图尔特·A·华莱士主席，罗伯特·L·穆迪，资深主席，系教授。病理学系 贝勒医学院免疫学教授和贝勒医学院杰出教授池川雅仁博士 大阪大学微生物病研究所。两位共同导师都是杰出的研究人员 生殖和老鼠遗传学领域。这项研究将主要在Matzuk博士的 贝勒医学院的实验室，这是德克萨斯医学中心的一家顶级研究机构。 蒙西韦拥有丰富的研究资源和合作机会。短期内，该奖项将 为Monsivais博士提供生殖生物学和小鼠方面的职业发展和研究培训 遗传学。 独立调查员。这些研究的数据将揭示编排母体的分子事件 和胚胎在植入过程中的相互作用，将改善女性的治疗选择 经历不孕不育和早孕丢失。

Project Summary Despite the high incidence of early pregnancy loss among women, its causes are not well-understood and the treatment options are limited. The endometrium is the first site of contact between the embryo and mother, therefore, understanding the molecular signature of the endometrium at the time of embryo implantation will help us develop therapies to prevent early pregnancy loss in women. Bone morphogenetic proteins (BMPs) are highly conserved factors of the TGFb superfamily that signal by binding to a heterodimeric receptor complex composed of a BMP type 1 receptor and type 2 receptor complex. After receptor binding and activation, SMAD1 and SMAD5 proteins are phosphorylated, form a complex with SMAD4, and translocate to the nucleus to control gene expression. We recently showed that signaling components of the TGFb family (ALK3, ALK5, BMP7 and follistatin) are critical for endometrial receptivity by controlling the endometrial response to the steroid hormones, estrogen (E2) and progesterone (P4). However, the mechanism linking the TGFb pathway and the endometrial response to the steroid hormones is not understood. The goals of this proposal are to determine how the downstream signaling components of the BMP pathway, the SMAD1 and SMAD5 transcription factors, control the response to E2 and P4 in the endometrium during the process of embryo implantation. We will use transgenic mice and human endometrial samples to fully delineate how SMAD1 and SMAD5 control the endometrial response to E2 and P4 during early pregnancy. This award will support the career development of Diana Monsivais, Ph.D., a Postdoctoral Associate and IRACDA Fellow at Baylor College of Medicine. The candidate will be co-mentored by Dr. Martin Matzuk, the Stuart A. Wallace Chair, Robert L. Moody, Sr. Chair, and Professor in the Dept. of Pathology & Immunology at Baylor College of Medicine and by Dr. Masahito Ikawa, Distinguished Professor at the Research Institute for Microbial Diseases in Osaka University. Both co-mentors are outstanding researchers in the fields of reproduction and mouse genetics. The research will be primarily performed in Dr. Matzuk’s laboratory at Baylor College of Medicine, a top research institution in the Texas Medical Center, providing Dr. Monsivais with abundant research resources and access to collaborations. In the short-term, the award will provide Dr. Monsivais with career development and research training in reproductive biology and mouse genetics. In the long-term, this award will support the candidate’s transition into a faculty position as an independent investigator. Data from these studies will reveal the molecular events that orchestrate maternal and embryonic interactions during implantation, and will improve the therapeutic options for women experiencing infertility and early pregnancy loss.