Investigating the role of Tumor Necrosis Factor-Receptor Associated Factor 3 Interacting Protein 2

项目总结 候选人是一名双重训练的牙周病科学家，致力于致力于 研究牙周病，改善口腔健康。牙周炎是一种多基因的炎性反应。 对牙龈表面的细菌病原体，影响美国47%的成年人 各州。这种常见的口腔疾病，如果没有有效的治疗，最终会导致牙齿脱落，并 与糖尿病等全身性疾病显著相关。一种全基因组关联分析 牙周炎研究发现肿瘤坏死因子受体相关因子3相互作用 蛋白2(TRAF3IP2)作为目的基因。TRAF3IP2功能障碍等关键基因引起 变异与高致病菌定义的牙周炎表型显著相关 TRAF3IP2是IL-17途径中的一个非冗余接头分子， 它在粘膜防御中起着关键作用。这项研究计划的目的是获取知识 TRAF3IP2介导的IL-17在牙龈屏障防御机制中的应答及其变异体诱导 IL-17途径的功能缺陷。候选假设TRAF3IP2-IL17信令丢失 损害口腔上皮屏障和粘膜炎症信号，促进反生菌 微生物群过度生长。这一假说将通过体外和体内遗传学方法进行验证。vbl.使用 Traf3ip2消融小鼠后，候选者将首先确定IL-17/TRAF3IP2途径的调控作用 牙周病原体诱导的小鼠牙槽骨的免疫反应和微生物群落结构 损失模型(Aim1)。然后，候选人将研究IL-17/TRAF3IP2途径在粘膜中的作用 IL-17调节紧密连接结构的物理屏障功能和机制(目标2)。候选人将会 进一步确定TRAF3IP2变异体对免疫应答的影响，其反映在转录和 基因工程人趋化因子合成和屏障功能的转录后调控 牙龈上皮细胞(AIM 3)。这项研究计划的实施需要额外的培训。 包括复合微生物群落结构分析、Th17/IL-17免疫生物学、上皮生物学和 分子基因组学。各领域专家的强大指导和 北卡罗来纳大学教堂山分校将促进这项研究提案的完成，并 加快应聘者的职业发展。其中概述的科学组成部分和培训 提案提供了一条途径，不仅可以实现候选人的短期目标，也就是过渡到 在终身教职跟踪教员职位上担任独立研究员，获得R01资金支持，但也是长期的 目标是更新对粘膜表面宿主-病原体相互作用的理解。专业知识 所取得的成果将有助于开发新的预防、诊断和治疗手段 改善牙周疾病，改善口腔健康。

PROJECT SUMMARY The candidate is a dual-trained periodontist scientist who is committed to an academic career dedicated to study periodontal disease and improve oral health. Periodontitis is a polygenetic, inflammatory response towards bacterial pathogens at the gingival surface and affects 47% of the adult population in the United States. This common oral disease, without effective management, eventually leads to tooth loss and is significantly associated with systemic conditions such as diabetes. Analysis of a Genome Wide Association Study (GWAS) for periodontitis has identified Tumor necrosis factor Receptor-Associated Factor 3 Interacting Protein 2 (TRAF3IP2) as a target gene of interest. TRAF3IP2 dysfunction, such as induced by key genetic variants, is significantly associated with a periodontal inflammation phenotype defined by a high pathogen burden in plaque and local inflammation.TRAF3IP2 is a non-redundant adaptor molecule in the IL-17 pathway, which plays a critical role in mucosal defense. The objective of this research proposal is to acquire knowledge of the TRAF3IP2-mediated IL-17 response in gingival barrier defense mechanisms and the variant-induced functional defects in the IL-17 pathway. The candidate hypothesizes that loss of TRAF3IP2-IL17 signaling compromises the oral epithelial barrier and mucosal inflammatory signature and promotes dysbiotic microbiome overgrowth. This hypothesis will be tested by both in vitro and in vivo genetic approaches. Using Traf3ip2 ablated mice, the candidate will first determine the role of the IL-17/TRAF3IP2 pathway-modulated immune response and microbial community structure in a periodontal pathogen-induced murine alveolar bone loss model (Aim1). The candidate will then investigate the role of the IL-17/TRAF3IP2 pathway in mucosal physical barrier function and mechanism of IL-17-regulated tight junction structure (Aim 2). The candidate will further determine the TRAF3IP2 variant effect on immune response as reflected by the transcriptional and post-transcriptional regulation of chemokine synthesis and barrier function in genetically engineered, human gingival epithelial cells (Aim 3). The implementation of this research proposal requires additional training including complex microbial community structure analysis, Th17/IL-17 immunobiology, epithelial biology and molecular genomics. Strong mentorship by experts in each field and the exceptional environment at the University of North Carolina at Chapel Hill will foster the accomplishment of this research proposal and expedite the career development of the candidate. The scientific component and training outlined in this proposal provide a pathway to achieving not only the candidate's short-term goal, which is to transition into an independent investigator at a tenure track faculty position with R01 funding support, but also the long-term goal, which is to update understanding of host-pathogen interactions at the mucosal surface. The expertise gained will facilitate the development of novel preventive, diagnostic and therapeutic means to tackle periodontal disease and improve oral health.