The Role of Interferon Regulatory Factor 8 (IRF8) in Periodontal Disease

干扰素调节因子 8 (IRF8) 在牙周病中的作用

• 批准号: 9903111
• 负责人: Vivek Thumbigere-Math
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-02 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9903111
• 关键词: Adult; Affect; Aging; Alveolar Bone Loss; Animal Model; Animals; Binding; Binding Sites; Biological Assay; Blood; Bone Resorption; Bone remodeling; C-terminal; Cell Differentiation process; Cells; ChIP-on-chip; ChIP-seq; Clinical; Community Health Services; Complement; Coupled; Crohn' s disease; Cytokine Signaling; DNA Binding; Data; Dental; Dental Clinics; Dental Records; Dental Schools; Dentin; Development; Development Plans; Diagnostic; Disease; Disease susceptibility; Economic Burden; Electrophoretic Mobility Shift Assay; Environment; Exhibits; Extracellular Matrix; Faculty; Family; Family member; Future; Genes; Gingiva; Goals; Grant; Heterodimerization; Histologic; Histology; Homeostasis; Host Defense; Human; IFN consensus sequence binding protein; Immune; Immune response; Immunohistochemistry; Impairment; In Situ Hybridization; In Vitro; Individual; Infection; Inflammatory; Inflammatory Response; Interferon Type II; Interleukin-1 beta; Interleukin-6; Intervention; Investigation; Knock-in Mouse; Knowledge; Lead; Maps; Matrix Metalloproteinases; Measurement; Measures; Mediating; Mentorship; Methods; Molecular; Morphology; Multiple Sclerosis; Mus; Mutation; Myeloid Cells; N-terminal; Osteoclasts; Pathogenesis; Pathology; Pathway interactions; Periodontal Diseases; Periodontal Ligament; Periodontitis; Periodontium; Phenotype; Positioning Attribute; Predisposition; Prevention strategy; Production; Proteins; Pulp Chambers; Research; Research Personnel; Research Project Grants; Research Training; Rheumatoid Arthritis; Roentgen Rays; Role; Root Resorption; Serum Markers; Signal Transduction; Stimulus; Structure; Systemic Lupus Erythematosus; TLR2 gene; TLR4 gene; TNF gene; TNFSF11 gene; Testing; Therapeutic Intervention; Tissue Sample; Tissues; Training; Training Activity; Transforming Growth Factor beta; Translating; Ulcerative Colitis; United States; United States National Institutes of Health; Variant; aged; antimicrobial; base; bone; career; career development; chronic inflammatory disease; clinical application; cytokine; exome sequencing; genome-wide; human subject; in vitro Assay; insight; kindred; laboratory experience; macrophage; microCT; microbial; monocyte; mouse model; multidisciplinary; mutant; novel; oral microbiome; osteoclastogenesis; periodontopathogen; proband; prognostic; programs; psychologic; public health relevance; receptor; research and development; risk variant; screening; skeletal; skills; social; tenure track; transcription factor; transcriptome sequencing

DESCRIPTION (provided by applicant): Periodontal disease, characterized by dysregulated immune response to oral microbiome, is one of the most prevalent chronic inflammatory diseases affecting humans. In the United States, periodontal disease affects approximately 46% of the adults aged 30 years and above, with 9% having severe periodontitis. The impact of periodontal disease in terms of social, psychological and economic burden on individuals, communities and health services is enormous. Despite these concerns, the molecular mechanisms regulating inflammatory-mediated tissue destruction in periodontal disease remains unclear, creating a critical knowledge gap in developing targeted interventions for periodontal disease. This K99/R00 application is aimed at advancing the fundamental knowledge of immunopathological mechanisms contributing to inflammatory-mediated tissue destruction in periodontal disease. Recently, the candidate has identified novel mutations in the interferon regulatory factor 8 gene (IRF8) that increase susceptibility to periodontal disease in humans and mice. The goals of the proposed research are to delineate the molecular mechanisms by which IRF8 functions to maintain a healthy periodontium and how specific mutations in IRF8 disrupt periodontal homeostasis, which will further contribute to better understanding of other inflammatory disorders such as rheumatoid arthritis, systemic lupus erythematosus, ulcerative colitis, Crohn's disease, and multiple sclerosis that have known risk alleles in IRF8. The proposed multi-disciplinary project capitalizes on novel IRF8 mutant animal models and human subjects available at the NIH. The applicant is a postdoctoral research fellow at the NIH and is highly qualified to lead this research program based on his research training in bone remodeling and periodontal disease, coupled with his clinical expertise as a board certified periodontist. The candidate's long-term career goal is to lead a productive research program that provides significant insights into periodontal disease pathogenesis, and translate those insights into tangible clinical applications such as diagnostic and prognostic screening tests, prevention strategies, and therapeutic interventions. The proposed project is an ideal starting point for the candidate to transition into an independent research career because it provides a framework for developing further skills necessary to accomplish the long-term goal. The proposed career development plan incorporates didactic coursework, laboratory training, and a structured mentorship plan to facilitate accomplishment of short-term goals, including development of a skill set for periodontal disease research, establishment of an independent research project, providing a pathway for obtaining a tenure-track faculty position at a top-tier dental school, and providing future opportunities to build on the proposed research. The applicant's institutional environment offers exceptional opportunities for research and career development training and is committed towards candidate's successful transition into an independent investigator.

描述(申请人提供)：牙周病，以口腔微生物群免疫反应失调为特征，是影响人类的最常见的慢性炎症性疾病之一。在美国，大约46%的30岁及以上的成年人患有牙周病，其中9%患有严重的牙周炎。牙周病对个人、社区和卫生服务造成的社会、心理和经济负担是巨大的。尽管有这些担忧，但调控牙周病炎症介导的组织破坏的分子机制仍不清楚，这在开发牙周病靶向干预措施方面造成了关键的知识缺口。K99/R00的应用旨在促进促进牙周病中炎症介导的组织破坏的免疫病理机制的基础知识。最近，这位候选人发现了干扰素调节因子8基因(IRF8)的新突变，这种突变会增加人类和小鼠患牙周病的易感性。拟议研究的目标是描述IRF8维持健康牙周组织的分子机制，以及IRF8的特定突变如何破坏牙周稳态，这将进一步有助于更好地了解其他炎症性疾病，如类风湿性关节炎、系统性红斑狼疮、溃疡性结肠炎、克罗恩病和多发性硬化症，这些疾病在IRF8中具有已知的风险等位基因。拟议的多学科项目利用了美国国立卫生研究院提供的新的IRF8突变动物模型和人类受试者。申请者是美国国立卫生研究院的博士后研究员，基于他在骨骼重塑和牙周病方面的研究培训，以及他作为委员会认证牙周科医生的临床专业知识，他非常有资格领导这项研究计划。候选人的长期职业目标是领导一个富有成效的研究计划，为牙周病的发病机制提供重要的见解，并将这些见解转化为切实的临床应用，如诊断和预后筛查测试、预防策略和治疗干预措施。拟议的项目是候选人过渡到独立研究职业生涯的理想起点，因为它 为进一步培养完成长期目标所需的技能提供了一个框架。拟议的职业发展计划包括教学课程、实验室培训和结构化的指导计划，以促进短期目标的实现，包括发展牙周病研究的技能集，建立独立的研究项目，为获得一流牙科学校的终身教职提供途径，并提供未来在拟议研究的基础上发展的机会。申请人的机构环境为研究和职业发展培训提供了绝佳的机会，并致力于使候选人成功地过渡到独立调查人员。

项目成果

Periodontitis in Chédiak-Higashi Syndrome: An Altered Immunoinflammatory Response.

Chédiak-Higashi 综合征中的牙周炎：免疫炎症反应改变。

• DOI: 10.1177/2380084417724117
• 发表时间: 2018
• 期刊: JDR clinical and translational research
• 作者: ThumbigereMath,V;Rebouças,P;Giovani,PA;Puppin-Rontani,RM;Casarin,R;Martins,L;Wang,L;Krzewski,K;Introne,WJ;Somerman,MJ;NocitiJr,FH;Kantovitz,KR
• 通讯作者: Kantovitz,KR