IL29 and IL28B Variants Associated with Periodontal Disease Pathogenesis

 描述（由申请人提供）：本资助申请题为“IL 29和IL 28 B变体与牙周病发病机制相关”，是在Steven Offenbacher（牙科学院）指导下的指导以患者为导向的研究职业发展奖（K23）提案。培训和研究计划代表了我的临床培训和新兴的转化研究的成果;研究项目集中在牙周病发病机制中面临的最紧迫的当前临床困境：遗传易感性。从全基因组关联研究（GWAS）获得的结果鉴定了对牙周病的几个方面重要的基因，特别是IL 29和IL 28 B，其参与调节响应细菌和病毒攻击的先天性和适应性免疫系统。 该职业发展奖的总体目标是为候选人提供必要的教学和体验式学习，以促进他向独立研究者的过渡，并确定IL 28 B和IL 29的次要等位基因变体与慢性牙周炎表达的临床相关性。目的1将用于确定SNP变体对支架诱导的生物膜过度生长期间牙周疾病表达和局部炎症反应的影响。该模型是经典实验牙龈炎模型的当代版本，将用于评价与显性等位基因变体相比，IL 28 B和IL 29 SNP变体对生物膜过度生长的临床反应的影响。目的2将在体外评估SNP变体对细胞介导的先天性炎症反应的影响。该反向翻译目的将评估IL 28 B和IL 29的次要等位基因SNP变体对树突细胞的细胞因子应答的影响。 为了实现这一建议的目标，候选人有机会获得一个独特的合作环境，包括牙周病学家，流行病学家，微生物学家，免疫学家，和生物统计学家从牙科，医学和Gillings公共卫生的资源学校。这些学校和个人之间有计划的联系，这将允许与专注于口腔健康的非常多样化的临床医生和研究人员进行持续的互动。 主要导师，史蒂芬奥芬巴赫是牙周病学教授在牙科学校。他通过NIDCR获得了NIH的资助，并在牙周研究的大多数领域（包括临床和基础科学）拥有专业知识，包括教育、系统性疾病、种植学、骨免疫学和遗传学。研究咨询委员会成员，里卡多·泰勒斯，卡里北，詹妮弗·韦伯斯特Cyriaque，和约翰·普莱瑟，每个人都带来了独特的优势，委员会。Teles博士在临床研究、牙周病发病机制以及微生物和宿主来源的生物标志物方面拥有专业知识。North博士的专长包括遗传流行病学和统计遗传学。Webster-Cyriaque博士是一位免疫学家，在口腔疾病的分子发病机制方面具有丰富的经验，并获得了NIH的资助。Preisser博士的主要合作研究领域是牙科，包括口腔流行病学和牙周病的生物学机制。他与奥芬巴赫集团合作多年。研究咨询委员会的成员都是各自领域的研究人员，他们将为研究战略计划的制定和执行提供见解，最重要的是通过我的职业发展计划提供指导。 在这个为期五年的奖项期间，目标是成为一名独立的科学家，对研究设计，人类受试者的伦理治疗以及基因组学在牙周病发病机制中的作用有更深入的了解。该赠款的五年框架将提供成为独立研究人员的工具和技能。候选人将使用本奖项完成的培训和研究，以准备竞争R 01补助金申请。

 DESCRIPTION (provided by applicant): This grant application titled, "IL29 and IL28B variants associated with periodontal disease pathogenesis", is a Mentored Patient-Oriented Research Career Development Award (K23) proposal under the guidance of Steven Offenbacher (UNC, School of Dentistry). The training and research plan represent outgrowths of my clinical training and emerging translational research; the research project centers on the most pressing current clinical dilemma faced in Periodontal Pathogenesis: genetic predisposition. Results obtained from a genome- wide association study (GWAS) identified genes important for several aspects of periodontal disease, particularly IL29 and IL28B, which are involved with modulating the innate and adaptive immune system in response to bacterial and viral challenge. The overall goals of this career development award are to provide the candidate with the necessary didactic and experiential learning to facilitate his transition to an independent investigator and to determine the clinical relevance of minor allelic variants of IL28B and IL29 with the expression of chronic periodontitis. Aim 1 will be used to determine the impact of SNP variants on periodontal disease expression and local inflammatory response during stent-induced biofilm overgrowth. This model, which is a contemporary version of the classic experimental gingivitis model, will be used to evaluate the influence of IL28B and IL29 SNP variants on the clinical response to biofilm overgrowth, as compared to the dominant allelic variants. Aim 2 will evaluate in vitro the impact of SNP variants on cell-mediated, innate inflammatory response. This reverse translational aim will evaluate the impact of the minor allelic SNP variants of IL28B and IL29 on cytokine responses of dendritic cells. To accomplish the goals of this proposal, the candidate has access to a unique collaborative environment including Periodontists, Epidemiologist, Microbiologists, Immunologists, and a Biostatistician from the resources of the UNC Schools of Dentistry, Medicine, and Gillings Public Health. There are programmatic links between these schools and individuals that will allow on-going interactions with a very diverse group of clinicians and researchers who focus on the oral health. The primary mentor, Steven Offenbacher is a Professor of Periodontology at the School of Dentistry. He has an established record of NIH funding through NIDCR with expertise in most areas of periodontal research (both clinical and basic science) including education, systemic diseases, implantology, osteoimmunology, andgenetics. The Research Advisory Committee members, Ricardo Teles, Kari North, Jennifer Webster-Cyriaque, and John Preisser, each bring distinct strengths to the Committee. Dr. Teles has expertise in clinical research, periodontal disease pathogenesis, and microbial and host-derived biomarkers. Dr. North expertise includes Genetic Epidemiology and Statistical Genetics. Dr. Webster-Cyriaque is an immunologist with experience with molecular pathogenesis in oral disease and an established record of NIH funding. Dr. Preisser's main collaborative research is in dentistry, including oral epidemiology and biological mechanisms of periodontal disease. He has collaborated with the Offenbacher group for several years. The members of the Research Advisory Committee are accomplished researchers in their respective fields and will provide insights into the development and execution of the research strategy plan, and most importantly provide mentoring through my developmental career plan. The goals during the this five-year award period are to become an independent scientist, with deeper understanding of research design, the ethical treatment of human subjects, and the role of genomics on periodontal disease pathogenesis. The five-year framework of the grant will provide the tools and skills to become an independent researcher. The candidate will use the training and research accomplished in this award to prepare for a competitive R01 grant application.