IInfection-Elicited Oral Bone Loss: TLR2, Ontogency, and Porphromonas Gingivalis

描述（由申请人提供）：牙周病是人类最常见的慢性传染病之一，据估计，仅在美国就有1亿人患有可测量的牙周骨质流失。重要的是，随着年龄的增长，牙周病在成年人中越来越常见，这表明个体发生影响牙周病的易感性和/或炎症进展。口腔里生活着无数的细菌；然而，牙龈卟啉单胞菌已被确定为与人类牙周病相关的主要病原。基于两项流行病学研究，toll样受体（TLRs；一组识别不同微生物模式的先天免疫受体）与人类牙周病的进展有关。然而，到目前为止，还没有进行实验研究来直接评估tlr的作用，或者在特定牙周病病原体的背景下，tlr介导的信号通路在口腔骨质流失中的作用。此外，缺乏关于模拟口腔骨质流失的长期模式，以应对感染的知识。在本研究中，我们提出：1-明确TLR2和TLR4在年龄相关的牙龈假单胞菌和菌毛先天免疫应答中的作用；2-明确myd88依赖性和myd88非依赖性信号在年龄相关的牙龈假单胞菌和菌毛先天免疫应答中的作用；3-明确TLR2和TLR4受体以及myd88依赖性和myd88非依赖性信号级联在牙龈假单胞菌感染小鼠年龄相关口腔骨质流失模式中的作用。

DESCRIPTION (provided by applicant): Periodontal disease is one of the most common chronic infectious diseases of humans and it has been estimated that in the United States alone 100,000,000 people possess measurable periodontal bone loss. Importantly, periodontal disease is increasingly more common in adults as they age suggesting that ontogeny impacts periodontal disease susceptibility and / or inflammatory progression. A myriad of bacteria inhabit the oral cavity; however, Porphyromonas gingivalis has been identified as a primary etiological agent associated with human periodontal disease. Based on two epidemiological studies, the toll-like receptors (TLRs; a group of innate immune receptors that recognize distinct microbial patterns) have been implicated in progression of human periodontal disease. However, to date, experimental studies have not been performed to directly assess the role for TLRs, or the adaptor molecules involved in TLR-mediated signaling in oral bone loss in the context of a specific periodontal disease pathogen. Moreover, there is a lack of knowledge regarding modeling long-term patterns of oral bone loss in response to infection. In this study, we propose 1- To define the role of TLR2 and TLR4 in the age-related innate immune response to P. gingivalis and fimbriae; 2- To define the role of MyD88-dependent and MyD88-independent signaling in the age-related innate immune response to P. gingivalis and fimbriae; and 3- To define the roles for the TLR2 and TLR4 receptors and MyD88-dependent and MyD88-independent signaling cascades in age-related oral bone loss patterns in mice in response to P. gingivalis infection. These studies will: 1- elucidate the contribution of ontogeny to the host inflammatory response to P. gingivalis in vitro; 2- define the age-related progression of oral bone loss in a murine model in response to P. gingivalis infection; and 3- and assess the contribution of TLR2 and TLR4, as well as TLR adaptor molecules including MyD88 in this response. These studies provide for a thorough examination of the mechanisms underlying the role played by specific TLR receptors to P. gingivalis-elicited inflammation and oral bone loss in the context of age.