Recurrent Pregnancy Loss (RPL) is defined as the loss of 2 or more consecutive clinical pregnancies. RPL is estimated to occur in up to 5% of women and can be attributed to clinically identifiable causes in only 50% of cases. Dysregulated immune function remains one of the most widely hypothesized, yet least understood, mechanisms contributing to RPL. Women with idiopathic RPL display elevated serum levels of cytotoxic cytokines. Further, decidualization of endometrial stromal cells, a process critical for successful embryo implantation, is dysregulated in the setting of RPL, associated with enhanced expression of inflammatory markers and reduced capacity to discriminate embryo quality. My work is focused on understanding the mechanisms driving embryo implantation and how they can be dysregulated in the setting of infertility. We have identified the evolutionarily conserved Notch signaling pathway as a critical mediator of decidualization in mice, non-human primates, and women. Notch signaling drives many developmental mechanisms along with regulation of the immune response and repair following tissue injury. In order to study the function of all Notch pathway signaling, I generated a uterine-specific conditional knockout mouse (Pgr-cre) for the canonical Notch receptor transcription factor, Recombination Signal Binding Protein-Jκ (Rbpj; Pgrcre/+Rbpjf/f; Rbpj c-KO). Initially, these mice display significant sub-fertility due, in part, due to impaired decidualization. Subsequently, Rbpj c-KO mice develop secondary infertility after pregnancy due to dysfunctional postpartumuterine repair. The objective of my dissertation work was to understand the mechanisms contributing to failed decidualization and postpartum repair in Rbpj c-KO mice. Additionally, I identified decreased RBPJ expression in the endometrium of women with RPL. Repeated embryo loss and endometrial repair are particularly relevant in the setting of RPL. Therefore, I used the Rbpj c-KO mouse as a model for RPL to determine the impact of Rbpj loss in the setting of dysfunctional postpartum repair to understand the effect on future pregnancy potential.
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