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

在哺乳动物中，许多细胞内信号通路调控着增殖、分化和细胞命运决定等过程，仔细地协调着子宫的发育和功能。河马信号通路通过其效应分子YAP和转录共激活子与PDZ结合基序(TAZ)的活性来调节这一过程。这一途径的异常调节与疾病的发生密切相关。我们最近在小鼠身上的工作显示了河马在调节慢性炎症和纤维化方面的潜在作用，包括在子宫中。河马是一条高度进化保守的途径。这表明，在奶牛中，子宫健康是繁殖成功的首要因素，它可能也依赖河马的子宫功能。这在加拿大尤其重要，因为在加拿大，奶牛业是一个非常有价值的行业。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，河马信号在牛子宫内膜炎的发生发展中起着重要作用，这是一种以子宫内膜炎症和纤维化为特征的疾病。在本提案中，我们提议在这些结果的基础上加以扩展。我们将首先研究河马分子(效应基因和靶基因)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河马信号在调节子宫炎症和子宫内膜炎发展中的作用。我们将确定细菌驱动的子宫炎症如何调节河马信号的激活。我们相信，我们的提案将确定调控牛子宫炎症和子宫疾病(如子宫内膜炎)发展的新分子机制。此外，我们的建议将为牛繁殖领域带来重大贡献，可能导致发现新的诊断和治疗方法，并为乳制品行业的全球可持续发展做出贡献。这一方案也具有很高的横向价值。来自该项目的后续发现和知识可能会应用于其他物种和研究主题(例如炎症的调节)。

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).