IL29 and IL28B Variants Associated with Periodontal Disease Pathogenesis

 描述(由申请人提供)：这份名为“IL29和IL28B与牙周病发病机制相关的IL29和IL28B变种”的资助申请，是在北卡罗来纳大学牙科学院Steven Offenbacher的指导下，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翻译研究的结果；该研究项目集中在牙周致病学目前面临的最紧迫的临床困境：遗传易感性。全基因组关联研究(Gwas)的结果确定了对牙周病的几个方面至关重要的基因，特别是IL29和IL28B，它们参与调节先天和适应性免疫系统，以应对细菌和病毒的挑战。 该职业发展奖的总体目标是为候选人提供必要的教学和经验学习，以促进他向独立研究者的过渡，并确定IL28B和IL29的微小等位基因变异与慢性牙周炎的临床相关性。目的1研究SNP变异体在支架诱导生物膜过度生长过程中对牙周病表达和局部炎症反应的影响。该模型是经典实验性牙周炎模型的当代版本，将用于评估IL28B和IL29SNP变异对生物膜过度生长的临床反应的影响，并与显性等位基因变异进行比较。目的2将在体外评估SNP变异体对细胞介导的先天炎症反应的影响。这个反向翻译目标将评估IL28B和IL29的次要等位基因SNP变体对树突状细胞细胞因子反应的影响。 为了实现这项建议的目标，候选人可以获得一个独特的协作环境，包括牙周科医生、流行病学家、微生物学家、免疫学家和来自北卡罗来纳大学牙科、医学和吉林斯公共卫生学院资源的生物统计学家。这些学校和个人之间有计划上的联系，这将允许与专注于口腔健康的非常不同的临床医生和研究人员群体进行持续互动。 主要导师史蒂文·奥芬巴赫是牙医学院的牙周学教授。他有通过NIDCR资助NIH的既定记录，在牙周研究的大多数领域(包括临床和基础科学)都有专业知识，包括教育、系统疾病、种植学、骨免疫学和遗传学。研究咨询委员会成员里卡多·特莱斯、卡里·诺斯、詹妮弗·韦伯斯特-塞里亚克和约翰·普赖瑟各自为委员会带来了不同的优势。Teles博士在临床研究、牙周病发病机制以及微生物和宿主衍生生物标记物方面拥有专业知识。诺斯博士的专长包括遗传流行病学和统计遗传学。韦伯斯特-西里亚克博士是一位免疫学家，在口腔疾病的分子发病机制方面有经验，并在NIH的资助方面有既定的记录。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已有数年。研究咨询委员会的成员在各自的领域都是有经验的研究人员，他们将对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发展职业规划提供指导。 在这个为期五年的获奖期内，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。赠款的五年框架将提供成为独立研究人员的工具和技能。候选人将利用在该奖项中完成的培训和研究，为竞争性的R01拨款申请做准备。

 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.