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

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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.