Elucidation of novel intracellular signaling mechanisms underlying uterine function and disease in cows.

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In mammals, numerous intracellular signaling pathways regulating processes such as proliferation, differentiation and cell fate determination carefully coordinate uterine development and function. The Hippo signaling pathway regulate such processes through the activity of their effector molecules: Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ). Dysregulations of this pathway is notably involved in the development of diseases. Our recent work in mice showed the roles of Hippo in regards to the potential regulation of chronic inflammation and fibrosis, including in the uterus. Hippo is a highly evolutionary conserved pathway. This suggests that dairy cattle, in which uterine health is primordial for reproductive success, may also rely on Hippo for uterine function. This is especially important in Canada, in which dairy farming is a highly valuable industry. However, available data concerning the roles of Hippo in the development of uterine diseases in cows is scarce. Our preliminary results suggest the implication of Hippo signaling in the development of bovine endometritis, a disease characterized by endometrial inflammation and fibrosis. In the present proposal, we propose to expand upon those results. We will first start by studying the expression of Hippo molecules (effectors and target genes) in the uterus of healthy cows during the post-partum period and cows with endometritis. We will then study the roles of Hippo signaling in the regulation of uterine inflammation and the development of endometritis through both in vitro and in vivo techniques. We will determine how the bacterial-driven inflammation in the uterus regulates the activation of Hippo signaling. We are confident that our proposal will identify novel molecular mechanisms regulating inflammation in the bovine uterus and the development of uterine diseases such as endometritis. Furthermore, our proposal will bring significant contributions to the field of bovine reproduction that could lead to the discovery of novel diagnostic and therapeutic approaches and contribute to the worldwide sustainability of the dairy industry. This program also have a high transversal value. The subsequent discoveries and knowledges from this program could potentially be applied to other species and research thematics (such as the regulation of inflammation).