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

描述（由申请人提供）：牙周病是影响人类最普遍的慢性炎症性疾病之一，其特征是对口腔微生物群的免疫反应失调。在美国，牙周病影响了大约46%的30岁及以上的成年人，其中9%患有严重的牙周炎。牙周病在社会、心理和经济负担方面对个人、社区和卫生服务的影响是巨大的。尽管存在这些担忧，但牙周病中调节炎症介导的组织破坏的分子机制仍不清楚，这在制定针对牙周病的靶向干预措施方面造成了关键的知识空白。这项K99/R00应用旨在推进炎症介导的牙周病组织破坏的免疫病理机制的基础知识。最近，该候选人发现了干扰素调节因子8基因（IRF8）的新突变，该突变增加了人类和小鼠对牙周病的易感性。这项研究的目标是描述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理解其他炎性疾病，如类风湿关节炎、系统性红斑狼疮、溃疡性结肠炎、克罗恩病和多发性硬化症，这些疾病已知有IRF8的风险等位基因。拟议的多学科项目利用NIH提供的新型IRF8突变动物模型和人类受试者。申请人是美国国立卫生研究院的博士后研究员，基于他在骨重塑和牙周病方面的研究训练，加上他作为董事会认证牙周病专家的临床专业知识，他非常有资格领导这个研究项目。候选人的长期职业目标是领导一个富有成效的研究项目，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实际的临床应用，如诊断和预后筛查测试，预防策略和治疗干预。提议的项目是一个理想的起点，为候选人过渡到一个独立的研究生涯，因为它

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.