Balancing expression of PRRs in epithelial innate immune responses to bacteria

描述（由申请人提供）：上皮组织作为宿主与外部环境（包括致病性和非致病性细菌）之间的第一道防线。在口腔中，上皮组织不断暴露于各种细菌，但大多数人保持健康的体内平衡。然而，很少有人知道这种自我平衡的关系是如何协调的。通过siRNA利用RNA干扰的初步数据表明，模式识别受体（PRR）之间存在补偿机制。此外，当PRR被激活时，其他PRR的表达增加。这些数据有力地表明，上皮细胞具有新的机制来平衡PRR的表达以响应细菌。在该提议中待测试的假设是PRR在暴露于口腔细菌时平衡其在上皮先天免疫中的应答，这取决于细菌的特征和致病性。这项工作的目标是了解上皮受体之间的交叉通讯以及参与上皮先天免疫中PRR交叉通讯的特异性信号传导途径。本提案将研究各种上皮细胞受体如何在诱导适当的上皮先天免疫应答中补偿彼此的激活或缺失。此外，这项建议将检查是否激活PRRs差异调节NF？B和MAPK信号通路，从而定制针对个体细菌的上皮先天免疫应答。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，因此可以合理地预期，在上皮对各种细菌的应答中，这些PRR之间存在交叉交流和平衡，以诱导适当的先天免疫应答。拟议的研究将有助于更好地了解口腔上皮细胞对致病性和非致病性细菌产生适当先天免疫反应的方式，为预防和治疗牙周病等口腔疾病的新治疗靶点提供指导。公共卫生相关性：要研究的具体目标包括研究各种上皮细胞受体如何在诱导适当的上皮先天免疫应答中补偿彼此的激活或缺失。这项建议还将调查，如果激活模式识别受体差异调节NF？B和MAPK信号通路，从而定制针对个体细菌的上皮先天免疫应答。拟议的研究将导致更好地了解口腔上皮细胞对致病性和非致病性细菌产生适当先天免疫反应的方式，为预防和治疗口腔疾病（如牙周病）的新治疗靶点提供指导。

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.