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

• 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
• 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

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.

项目摘要 候选人是一个双重训练牙周科学家谁是致力于学术生涯，致力于 研究牙周病和改善口腔健康。牙周炎是一种多基因的炎症反应 对牙龈表面的细菌病原体，并影响美国47%的成年人口 States.这种常见的口腔疾病，没有有效的管理，最终导致牙齿脱落， 与全身性疾病如糖尿病显著相关。全基因组关联分析 牙周炎的研究（GWAS）已经确定了肿瘤坏死因子受体相关因子3相互作用 蛋白2（TRAF 3 IP 2）作为目标靶基因。TRAF 3 IP 2功能障碍，如由关键遗传因素诱导的 变异，与牙周炎表型显著相关， TRAF 3 IP 2是IL-17途径中的非冗余衔接分子， 其在粘膜防御中起关键作用。本研究计划的目的是获取知识 TRAF 3 IP 2介导的IL-17应答在牙龈屏障防御机制和变体诱导的 IL-17通路的功能缺陷。该候选人假设TRAF 3 IP 2-IL 17信号转导的缺失 损害口腔上皮屏障和粘膜炎症特征并促进生态失调 微生物群落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 在Traf 3 ip 2消融的小鼠中，候选者将首先确定IL-17/TRAF 3 ip 2通路调节的IL-17/TRAF 3 ip 2通路的作用。 牙周致病菌诱导小鼠牙槽骨免疫反应及微生物群落结构 损失模型（Aim 1）。然后，候选人将研究IL-17/TRAF 3 IP 2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（目的2）。候选人将 进一步确定TRAF 3 IP 2变体对免疫应答的影响，如转录和 趋化因子合成的转录后调节和基因工程人的屏障功能 牙龈上皮细胞（Aim 3）。实施这项研究建议需要额外的培训 包括复杂微生物群落结构分析、Th 17/IL-17免疫生物学、上皮生物学和 分子基因组学每个领域的专家都提供了强大的指导， 位于查佩尔山的北卡罗来纳州大学将促进本研究提案的完成， 加快候选人的职业发展。本报告中概述的科学组成部分和培训 提案提供了一个途径，不仅实现候选人的短期目标，这是过渡到一个 在R 01资金支持的终身教职职位的独立调查员，但也长期 目的是更新对粘膜表面宿主-病原体相互作用的理解。的专门知识 这将有助于开发新的预防、诊断和治疗手段， 牙周病和改善口腔健康。