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

SMAD1 和 SMAD5 在激素反应、子宫内膜容受性和腺体功能中的作用

基本信息

批准号：
10468933
负责人：
Diana Monsivais
金额：
$ 24.4万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10468933
关键词：
Activins Affect Age Award BMP7 gene Binding Biological Bone Morphogenetic Proteins Cell Nucleus Cells Collaborations Complex Data Decidual Cell Reactions Defect Development Doctor of Philosophy Early Intervention Embryo Endometrial Endometrial Stromal Cell Endometrium Estrogen Receptors Estrogens Event Faculty Family Fellowship Female Female infertility Female sterility Fertility Follistatin Funding Gene Expression Genetic Transcription Genomics Goals Hormonal Hormones Human Immunology Impairment Incidence Infertility Institution Journals K-Series Research Career Programs Laboratories Lead Ligands Link MADH2 gene MADH4 gene Medical center Medicine Mentors Molecular Molecular Profiling Molecular Target Mothers Mus Mutant Strains Mice National Institute of Child Health and Human Development Organ Paper Pathology Pathway interactions Phase Phenotype Positioning Attribute Postdoctoral Fellow Pre-Eclampsia Pregnancy Prevention strategy Process Progesterone Progesterone Receptors Proteins Puberty Publishing Receptor Activation Reproduction Reproductive Biology Research Research Institute Research Personnel Research Priority Research Proposals Research Training Resources Role Sampling Scientist Signal Pathway Signal Transduction Site Study models TGF-beta type I receptor Texas Therapeutic Time Tissues Transgenic Mice United States National Institutes of Health Universities Uterine Gland Uterus Woman antagonist bone morphogenetic protein receptors career career development college design distinguished professor early pregnancy early pregnancy loss experience failure Implantation genome-wide genome-wide analysis gland development implantation improved inhibitor laboratory curriculum lectures meetings microbial disease mouse genetics mouse model natural Blastocyst Implantation novel prevent professor receptor receptor binding reproductive reproductive function reproductive tract research study response small molecule steroid hormone therapy development transcription factor transcriptome sequencing treatment strategy undergraduate student

项目摘要

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.

项目摘要尽管女性妊娠早期丧生的发生率很高，但其原因并不理解为治疗方案有限。子宫内膜是胚胎和因此，母亲在胚胎时了解子宫内膜的分子特征植入将有助于我们开发疗法，以防止女性提早怀孕。骨形态发生蛋白（BMP）是TGFB超家族的高度保守因子，该因素通过与由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，SMAD1和SMAD5蛋白是磷酸化的，形成了一个复合物与 Smad4，并转移到核中以控制基因表达。我们最近显示了信号 TGFB家族（ALK3，ALK5，BMP7和Follistatin）的成分对于通过子宫内膜接受至关重要控制子宫内膜激素，雌激素（E2）和孕酮（P4）。然而，连接TGFB途径和子宫内膜反应与立体激素的机制不是理解齿。该提案的目标是确定如何的下游信号传导组件 BMP途径，SMAD1和SMAD5转录因子，控制对E2和P4的响应在胚胎植入过程中子宫内膜。我们将使用转基因小鼠和人子宫内膜样品完全描述了SMAD1和SMAD5如何控制对E2和P4的子宫内膜反应早期怀孕。该奖项将支持博士后Diana Monsivais博士的职业发展贝勒医学院的助理和IRACDA研究员。候选人将由马丁博士委托 Matzuk，Stuart A. Wallace主席，高级主席Robert L. Moody，病理学系教授贝勒医学院的免疫学和Masahito Ikawa博士，杰出教授大阪大学微生物疾病研究所。这两个副主持人都是杰出的研究人员繁殖和小鼠遗传学领域。该研究将主要在Matzuk博士的德克萨斯医学中心的顶级研究机构贝勒医学院实验室，为博士提供拥有丰富的研究资源和合作访问的Monsivais。在短期内，该奖项将向Monsivais博士提供生殖生物学和鼠标的职业发展和研究培训遗传学。从长远来看，该奖项将支持候选人过渡到教师职位独立研究者。来自这些研究的数据将揭示精心策划母体的分子事件和植入过程中的胚胎相互作用，并将改善女性的治疗选择经历不孕症和早期妊娠丧失。