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

在哺乳动物中，许多调节增殖、分化和细胞命运决定等过程的细胞内信号通路精心协调子宫的发育和功能。Hippo信号通路通过其效应分子的活性来调节这些过程：yes相关蛋白（YAP）和带pdz结合基序的转录共激活因子（TAZ）。该通路的失调与疾病的发生密切相关。我们最近在小鼠身上的研究表明，Hippo在慢性炎症和纤维化的潜在调节中发挥了作用，包括在子宫中。河马是一种高度进化的保守途径。这表明，奶牛的子宫健康对繁殖成功至关重要，可能也依赖于河马的子宫功能。这在加拿大尤其重要，因为奶牛养殖是一个非常有价值的产业。然而，关于河马在奶牛子宫疾病发展中的作用的现有数据很少。我们的初步结果表明，Hippo信号在牛子宫内膜炎（一种以子宫内膜炎症和纤维化为特征的疾病）的发展中具有重要意义。在本提案中，我们提议扩大这些结果。我们将首先研究Hippo分子（效应器和靶基因）在产后健康奶牛和子宫内膜炎奶牛子宫中的表达。然后，我们将通过体外和体内技术研究Hippo信号在子宫炎症和子宫内膜炎发展中的调节作用。我们将确定子宫中细菌驱动的炎症如何调节Hippo信号的激活。我们有信心，我们的建议将确定新的分子机制调节炎症在牛子宫和发展的子宫疾病，如子宫内膜炎。此外，我们的建议将为牛生殖领域带来重大贡献，可能导致发现新的诊断和治疗方法，并为全球乳制品行业的可持续性做出贡献。该方案还具有较高的横向价值。该计划的后续发现和知识可能会应用于其他物种和研究主题（如炎症调节）。

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).