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

研究肿瘤坏死因子-受体相关因子 3 相互作用蛋白 2 的作用

基本信息

批准号：
10180936
负责人：
Shaoping Zhang
金额：
$ 24.11万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10180936
关键词：
16S ribosomal RNA sequencing Actinobacillus actinomycetemcomitans Adaptor Signaling Protein Address Adult Affect Alleles Alveolar Bone Loss Biological Assay Biology CRISPR/Cas technology Cells Clinical Co-Immunoprecipitations Code Complex Data Defect Defense Mechanisms Development Diabetes Mellitus Diagnostic Disease Environment Enzyme-Linked Immunosorbent Assay Epithelial Epithelial Cells Exhibits Faculty Feedback Flow Cytometry Fluorescence Fostering Functional disorder Funding Genes Genetic Genetic Engineering Genetic Transcription Genomics Gingiva Goals Health Homeostasis Human IL17 Signaling Pathway IL17 gene Immune Immune response Immunobiology Immunologic Surveillance Immunoprecipitation In Vitro Inflammation Inflammatory Inflammatory Response Interleukin-17 Intervention Knock-out Knockout Mice Knowledge Linkage Disequilibrium Mediating Mentorship Messenger RNA Modeling Molecular Mouth Diseases Mucosal Immune Responses Mucous Membrane Mus Necrosis Neutrophil Infiltration North Carolina Oral Oral health Pathway interactions Patients Periodontal Diseases Periodontitis Pharmacology Phase Phenotype Play Population Porphyromonas gingivalis Positioning Attribute Post-Transcriptional Regulation Preventive Preventive treatment Production Proteins RNA Regulation Research Personnel Research Proposals Role Scientist Signal Pathway Signal Transduction Structure Surface Systemic disease TNF Receptor-Associated Factors TNF gene TRAF2 gene TRAF6 gene Testing Therapeutic Tight Junctions Tissues Tooth Loss Tracer Training Transcriptional Activation Transcriptional Regulation United States Universities Update Variant Wild Type Mouse career career development chemokine cytokine dysbiosis genetic approach genetic variant genome wide association study improved in vivo individualized medicine interest interleukin-22 intestinal epithelium knock-down loss of function mRNA Stability member microCT microbial microbial community microbial host microbiome neutrophil novel occludin oral cavity epithelium pathogen pathogenic bacteria periodontopathogen preclinical study prevent receptor recruit response risk variant tenure track tool

项目摘要

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.

项目概要候选人是一位接受过双重培训的牙周病科学家，致力于学术生涯研究牙周疾病并改善口腔健康。牙周炎是一种多基因的炎症反应牙龈表面的细菌病原体，影响着美国 47% 的成年人国家。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，与糖尿病等全身性疾病密切相关。全基因组关联分析牙周炎研究 (GWAS) 已确定肿瘤坏死因子受体相关因子 3 相互作用蛋白质 2 (TRAF3IP2) 作为感兴趣的靶基因。 TRAF3IP2 功能障碍，例如由关键遗传引起的变异体，与高病原体定义的牙周炎症表型显着相关斑块和局部炎症的负担。TRAF3IP2是IL-17途径中的非冗余接头分子，它在粘膜防御中起着至关重要的作用。本研究计划的目的是获取知识 TRAF3IP2 介导的牙龈屏障防御机制中的 IL-17 反应以及变异诱导的 IL-17 通路的功能缺陷。候选者假设 TRAF3IP2-IL17 信号传导缺失损害口腔上皮屏障和粘膜炎症特征并促进菌群失调微生物组过度生长。这一假设将通过体外和体内遗传方法进行检验。使用 Traf3ip2 消融小鼠，候选者首先会确定 IL-17/TRAF3IP2 通路调节的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（目标1）。然后，考生将研究 IL-17/TRAF3IP2 通路在粘膜中的作用。 IL-17 调节的紧密连接结构的物理屏障功能和机制（目标 2）。候选人将进一步确定 TRAF3IP2 变异对免疫反应的影响，如转录和基因工程、人类趋化因子合成和屏障功能的转录后调控牙龈上皮细胞（目标 3）。本研究计划的实施需要额外的培训包括复杂的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。各领域专家的大力指导以及卓越的环境北卡罗来纳大学教堂山分校将促进这项研究计划的完成，并加快候选人的职业发展。本节概述的科学内容和培训提案不仅提供了实现候选人短期目标的途径，即过渡到独立研究员，在 R01 资金支持下担任终身教授职位，而且也是长期的目标是更新对粘膜表面宿主与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、诊断和治疗手段来解决牙周疾病并改善口腔健康。