The Role of Recombination Signal Binding Protein-J-kappa in Pregnancy

Michigan State University, East Lansing MI

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Abstract

? DESCRIPTION (provided by applicant): According to the CDC, 6% of married women between the ages of 15-44 are infertile, and 12.1% of women display difficulties getting pregnant or carrying a pregnancy to term. Embryo implantation defects contribute to over 75% of failed pregnancies and represent the major obstacle to the success of assisted reproductive technologies used in the management of infertile patients. Despite the profound impact of implantation failure on fertility, the signaling events necessary for successful embryo implantation remain unknown. The objective of our work is to understand the complex mechanisms by which the developing embryo communicates with the uterus to initiate attachment and invasion in a synchronous manner. Identifying novel pathways during this critical time period for the establishment of pregnancy will be essential for the improvement of pregnancy rates in infertility management. One of the primary responses initiated by the embryo during attachment and invasion is the transformation of the uterine stromal cells into specialized decidual cells. Impaired decidualization has been associated with recurrent pregnancy loss, preeclampsia, preterm labor, and intrauterine growth retardation. The Notch signaling pathway has been implicated in many developmental processes requiring cellular differentiation and proliferation, both mechanisms, which are important for decidualization. Our laboratory has identified that the canonical Notch pathway transcription factor, Recombination Signal Binding Protein-J? (RBP-J), is essential for ensuring successful pregnancy through regulating both decidualization and implantation, in part through promoting progesterone receptor and STAT3 signaling. Additionally, we have shown a role for RBP-J in controlling proper immune signaling for postpartum repair of the uterus. Dysregulated postpartum uterine repair is associated with infertility and downregulation of interleukin 6 (IL-6), a STAT3 regulator. The goal of this proposa is to determine the mechanisms by which RBP-J regulates decidualization and embryo implantation and promotes postpartum uterine repair. In Specific Aim 1, we will focus on the role of RBP-J in the initiation of pregnancy, specifically decidualization and embryo attachment. Studies will be conducted in our mouse model in which RBP-J has been ablated in progesterone receptor positive uterine cells and in Human Uterine Fibroblast (HUF) cells, which can be induced to undergo decidualization in vitro, to determine the translational relevance of our proposed mouse studies to human fertility. Also, the impact of therapeutic replacement of progesterone on rescuing fertility in our RBPJ-ablated mice will be evaluated. In Specific Aim 2, we will characterize postpartum repair in the setting of RBP-J- ablation, with a carefully designed time-course evaluation of key modulators of post-partum repair by specific populations of immune cells and cytokines. Further, we will determine the impact of postpartum repair failure on subsequent pregnancies. These studies will set precedence for studying the Notch signaling pathway as it relates to human infertility with implications for improving therapeutic management of infertile couples.