Molecular Genetics and Immunoregulatory mechanisms of PFAPA syndrome

描述（由申请人提供）：该提案描述了一个为期5年的培训计划，以发展医生-科学家的职业生涯。首席研究员在布法罗大学完成了肿瘤免疫学博士论文，并在加州大学圣地亚哥分校完成了儿科住院医师和过敏/免疫学奖学金培训。她将通过专注的职业发展计划和分子遗传学培训来扩展她的科学技能，并将其应用于儿科免疫失调。哈尔·霍夫曼博士是加州大学圣地亚哥分校的儿科和医学教授，他将指导首席研究员的科学和职业发展。霍夫曼博士是全球公认的自身炎症性疾病的领导者。一个由科学家组成的咨询委员会将提供额外的职业和项目指导，其中包括在儿科疾病基因组学方面具有专长的凯利·弗雷泽（Kelly Frazer）博士。此外，密集的讲习班、研讨会、期刊俱乐部和特定的实验室技术培训将伴随充足的受保护的研究时间。加州大学圣地亚哥分校儿科学系的学术环境支持独立的转化研究人员的发展。科学研究将集中于周期性发热、口疮性口炎、咽炎和腺炎（PFAPA）综合征的遗传和免疫调节机制，这是一种儿童期全身性炎症性疾病，其特征是在健康儿童中反复发作发烧、口咽体征、宫颈腺炎和白细胞增多。PFAPA的潜在病因尚不清楚，治疗方法有限；这两个问题都会对患者及其家属的生活质量产生负面影响。该项目的具体目标是：1)通过收集有多名成员有PFAPA病史的家庭的DNA，确定PFAPA综合征的遗传基础；2)研究扁桃体切除术后PFAPA患者组织中的基因表达模式，重点关注il -1相关通路和B细胞；3)评估扁桃体中DNA甲基化和组蛋白乙酰化事件在PFAPA发病机制中的调节作用。

DESCRIPTION (provided by applicant): This proposal describes a 5-year training program for the development of a career as a physician- scientist. The principal investigator has completed a PhD thesis at the University at Buffalo in tumor immunology, and Pediatric residency and Allergy/Immunology fellowship training at the University of California at San Diego. She will expand upon her scientific skills through a focused career development plan and training in molecular genetics as applied to immune dysregulation in pediatrics. Dr. Hal Hoffman is a Professor of Pediatrics and Medicine at UC San Diego and will mentor the principal investigator's scientific and career development. Dr. Hoffman is a globally recognized leader in autoinflammatory disorders. An advisory committee of scientists, including Dr. Kelly Frazer who has expertise in the role of genomics in pediatric disease, will provide additional career and project guidance. In addition, intensive workshops, seminars, journal clubs, and specific laboratory technique training will accompany ample protected research time. The academic environment in the Department of Pediatrics at UCSD supports the development of independent, translational investigators. Scientific investigations will focus on the genetic and immunoregulatory mechanisms of Periodic Fever, Aphthous stomatitis, Pharyngitis and Adenitis (PFAPA) syndrome, a systemic inflammatory disorder of childhood characterized by recurrent episodes of fever, oropharyngeal signs, cervical adenitis and leukocytosis in otherwise healthy children. The underlying etiology of PFAPA is unknown and therapies are limited; both are issues which negatively impact the quality of life for patients and their families. The specific goals of this project are: 1) to identify the genetic basis of PFAPA syndrome using DNA collected from families with multiple members that have a history of PFAPA, 2) to investigate the patterns of gene expression in tissue from PFAPA patients undergoing tonsillectomy with a focus on IL-1-related pathways and B cells, and 3) to evaluate the role of DNA methylation and histone acetylation events in tonsils as a regulatory mechanism in the pathogenesis of PFAPA.