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， 治疗选择有限。子宫内膜是胚胎与子宫内膜接触的第一个部位。 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治疗方法，以防止妇女早孕丢失。骨 形态发生蛋白（BMP）是TGF β超家族的高度保守的因子，其通过结合TGF β 1而发出信号。 由BMP 1型受体和2型受体复合物组成的异二聚体受体复合物。后 受体结合和激活时，SMAD1和SMAD5蛋白被磷酸化，与 SMAD4，并易位到细胞核中控制基因表达。我们最近发现， TGF β家族的组分（ALK 3、ALK 5、BMP 7和卵泡抑素）通过以下途径对子宫内膜容受性至关重要： 控制子宫内膜对类固醇激素雌激素（E2）和孕激素（P4）的反应。然而，在这方面， TGF β通路和子宫内膜对类固醇激素反应的联系机制不是 明白该提案的目标是确定如何将下行信令组件的 BMP通路，SMAD1和SMAD5转录因子，控制着细胞中对E2和P4的反应。 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 样本，以充分描述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Diana Monsivais博士的职业发展，博士后 贝勒医学院副院长和IRACDA研究员。候选人将由马丁博士共同指导 Matzuk，the Stuart A.华莱士主席，罗伯特L。穆迪，高级主席，并在系教授。病理学& 贝勒医学院的免疫学和Masahito Ikawa博士， 大坂大学微生物疾病研究所。两位共同导师都是杰出的研究人员， 生殖和小鼠遗传学领域。这项研究将主要在Matzuk博士的 贝勒医学院的实验室，一个顶级的研究机构在得克萨斯州医学中心，提供博士。 Monsivais拥有丰富的研究资源和合作机会。在短期内，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 遗传学从长远来看，这个奖项将支持候选人的过渡到教师的立场， 独立调查员这些研究的数据将揭示在哺乳动物中， 和胚胎在植入过程中的相互作用，并将改善妇女的治疗选择 不孕和早孕流产

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.