Genetic variation in T-cell regulatory molecules and JRA

描述（由申请人提供）： 幼年型类风湿性关节炎（JRA）是儿童最常见的慢性疾病之一，影响美国约50，000名儿童。JRA的病因和发病机制很复杂，但显然有遗传成分。主要组织相容性复合体的基因和对JRA的易感性之间的关联已经很好地建立，尽管致病性遗传变异的鉴定，更不用说翻译来改善临床实践了。在过去的十年中，直接和间接的证据表明，活化的T细胞的作用，特别是在JRA的发病机制中的Th 1表型。该项目的目标是确定编码T细胞调节分子的基因的遗传变异是否有助于JRA易感性、发病机制和治疗结果的变化。这将通过两个具体目标来实现。1.分析编码参与T细胞调节的配体-受体对的基因的遗传多样性。2.检测识别的遗传变异与JRA易感性和/或JRA的可变表达率之间的关联和连锁。这些研究将使用代表美国最大JRA患者集合的3个不同队列进行：（1）140个同胞与JRA（2）500个单例与JRA及其父母和（3）新确定的情况下，从登记的650多个JRA患者生活在山间西部。一个为期五年的指导计划，将结合教学和研究培训，并将由两个既定的科学家在犹他州大学的指导。通过美国国立卫生研究院资助的K30奖，犹他州大学综合临床研究中心提供了一个独特的临床研究培训教学计划，重点是人类疾病的遗传基础。该计划包括访问资源，如多用户核心设施，大学的大型研究中心和大学医院的指定单位，为成熟的临床研究人员提供具体的指导密集研究经验。因此，犹他州大学为最大限度地发挥本研究和本申请人的潜力提供了理想的环境。

DESCRIPTION (provided by applicant): Juvenile rheumatoid arthritis (JRA) is one of the most common chronic conditions of children affecting approximately 50,000 children in the U.S. The etiology and pathogenesis of JRA is complex, though there is clearly a genetic component. Associations between the genes of the major histocompatibility complex and susceptibility to JRA are well established, though identification of causal genetic variants, much less translation to improve clinical practice has not been forthcoming. Over the last decade, direct and indirect evidence has pointed to a role of activated T-cells, particularly of the Th1 phenotype in the pathogenesis of JRA. The goal of this project is to determine whether genetic variation in genes encoding T-cell regulatory molecules contributes to variation in JRA susceptibility, pathogenesis and treatment outcome. This will be accomplished via two specific aims. 1. Analyze genetic diversity in genes encoding ligand-receptor pairs involved in T-cell regulation. 2. Test for association and linkage between the genetic variants identified and susceptibility to JRA and or/variable expressivity of JRA. These studies will be conducted using 3 different cohorts representing the largest collection of JRA patients in the U.S.: (1)140 sibpairs with JRA (2) 500 singletons with JRA and their parents and (3) cases newly ascertained from a registry of more than 650 JRA patients living in the Intermountain West. A five year mentored program is proposed that will incorporate both didactic and research training and will be guided by two established scientists at the University of Utah. Through a NIH funded K30 award, the University of Utah General Clinical Research Center provides a unique didactic program of training in clinical research focused on the inherited basis of human disease. This program incorporates access to resources such as multi-user core facilities, large research centers at the University, and a designated unit in the University Hospital, with specific mentored intensive research experience for maturing clinical investigators. Thus, the University of Utah provides an ideal environment for maximizing the potential of this study and this applicant.