Balancing expression of PRRs in epithelial innate immune responses to bacteria

描述（由申请人提供）：上皮组织是宿主与外部环境（包括致病菌和非致病菌）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，但大多数个体保持健康的体内平衡。然而，人们对这种平衡关系是如何协调的知之甚少。通过siRNA利用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的表达也会增加。这些数据强烈表明，上皮细胞在对细菌的反应中具有平衡PRRs表达的新机制。本提案要验证的假设是，PRRs在暴露于口腔细菌后，根据细菌的特征和致病性平衡其在上皮先天免疫中的反应。这项工作的目的是了解上皮受体之间的交叉通讯，以及在上皮先天免疫中参与PRR交叉通讯的特定信号通路。本研究将探讨各种上皮细胞受体如何在诱导适当的上皮先天免疫反应中补偿彼此的激活或缺失。此外，该提案将研究PRRs的激活是否对NF？B和MAPK信号通路，从而定制上皮先天免疫应答个体细菌。由于细菌具有多种微生物相关分子模式，上皮细胞表达多种PRRs，因此我们有理由认为，在上皮细胞对各种细菌的应答中，这些PRRs之间存在交叉交流和平衡，以诱导适当的先天免疫应答。这些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提供新的治疗靶点。公共卫生相关性：研究的具体目的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反应时补偿彼此的激活或缺失。本研究还将探讨模式识别受体的激活是否对NF？B和MAPK信号通路，从而定制上皮先天免疫应答个体细菌。本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.