Balancing expression of PRRs in epithelial innate immune responses to bacteria

描述(申请人提供)：上皮组织是宿主与外界环境之间的第一道防线，包括致病细菌和非致病细菌。在口腔中，口腔上皮组织经常暴露在各种细菌中，但大多数人都保持着健康的动态平衡。然而，关于这种自我平衡关系是如何协调的，人们知之甚少。通过siRNA进行RNA干扰的初步数据表明，模式识别受体(PRRs)之间存在补偿机制。此外，当一个PRR被激活时，其他PRR的表达增加。这些数据有力地表明，上皮细胞有新的机制来平衡PRRs的表达，以应对细菌的反应。这一建议中要检验的假设是，PRRs在暴露于口腔细菌时平衡其在上皮天然免疫中的反应，这取决于细菌的特征和致病性。这项工作的目的是了解上皮受体之间的交叉通讯，以及参与上皮天然免疫中PRR交叉通讯的特定信号通路。这项建议将研究不同的上皮细胞受体如何在诱导适当的上皮固有免疫反应中相互补偿激活或缺失。此外，这项建议将检验PRRs的激活是否以不同的方式调节NF？B和MAPK信号通路，从而调整上皮细胞对单个细菌的先天免疫反应。由于细菌具有多种微生物相关的分子模式，并且上皮细胞表达多种PRR，因此有理由预期这些PRR在上皮细胞对不同细菌的反应中存在交叉沟通和平衡，以诱导适当的先天性免疫反应。拟议的研究将有助于更好地理解口腔上皮细胞对致病和非致病细菌产生适当的先天免疫反应的方式，为预防和治疗口腔疾病(如牙周病)提供新的治疗靶点。公共卫生相关性：要研究的具体目标包括调查不同的上皮细胞受体如何在诱导适当的上皮天然免疫反应中相互补偿激活或缺失。这项提议还将调查模式识别受体的激活是否以不同的方式调节NF？B和MAPK信号通路，从而定制针对单个细菌的上皮先天性免疫反应。拟议的研究将有助于更好地理解口腔上皮细胞对致病和非致病细菌产生适当的先天免疫反应的方式，为预防和治疗口腔疾病(如牙周病)提供新的治疗靶点。

DESCRIPTION (provided by applicant): Epithelial tissues function as the first line of defense between the host and the outside environment, which includes pathogenic and non-pathogenic bacteria. In the oral cavity, epithelial tissues are constantly exposed to a variety of bacteria, but most individuals maintain a healthy homeostasis. However, little is known about how this homeostatic relationship is orchestrated. Preliminary data utilizing RNA interference via siRNA suggest that compensatory mechanisms exist among Pattern Recognition Receptors (PRRs). Additionally, when a PRR is activated, the expression of other PRRs increases. These data strongly suggest that epithelial cells have novel mechanisms to balance expression of PRRs in response to bacteria. The hypothesis to be tested in this proposal is that PRRs balance their responses in epithelial innate immunity upon exposure to oral bacteria depending on the characteristics and pathogenicity of the bacteria. The goal of this work is to understand cross- communication between epithelial receptors as well as the specific signaling pathways that are involved in the PRR cross-communication in epithelial innate immunity. This proposal will investigate how various epithelial cell receptors compensate for the activation or absence of one another in inducing appropriate epithelial innate immune responses. In addition, this proposal will examine if activation of PRRs differentially regulate the NF?B and MAPK signaling pathways, thus tailoring epithelial innate immune responses to individual bacterium. Since bacteria have multiple Microbial-Associated Molecular Patterns and epithelial cells express multiple PRRs, it is reasonable to expect that there is cross-communication and balancing between these PRRs in epithelial responses to various bacteria in order to induce appropriate innate immune responses. The proposed studies will lead to a better understanding of the way oral epithelia produce appropriate innate immune responses to pathogenic and non-pathogenic bacteria, guiding a way to new therapeutic targets to prevent and treat oral diseases, such as periodontal disease. PUBLIC HEALTH RELEVANCE: The specific aims to be studied include investigation of how various epithelial cell receptors compensate for the activation or absence of one another in inducing appropriate epithelial innate immune responses. This proposal will also investigate if activation of pattern-recognition receptors differentially regulate the NF?B and MAPK signaling pathways, thus tailoring epithelial innate immune responses to individual bacterium. The proposed studies will lead to a better understanding of the way oral epithelia produce appropriate innate immune responses to pathogenic and non- pathogenic bacteria, guiding a way to new therapeutic targets to prevent and treat oral diseases, such as periodontal disease.