Genetic variation in T-cell regulatory molecules and JRA

T 细胞调节分子和 JRA 的遗传变异

• 批准号: 6777876
• 负责人: SAMPATH PRAHALAD
• 金额: $ 13.47万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6777876
• 关键词: T cell receptor; T lymphocyte; antigens; child (0-11); clinical research; disease /disorder etiology; family genetics; gene interaction; genetic polymorphism; genetic screening; genetic susceptibility; human genetic material tag; immunopathology; immunoregulation; juvenile rheumatoid arthritis; leukocyte activation /transformation; patient oriented research; pediatrics; protein structure function; quantitative trait loci; siblings; statistics /biometry

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.

描述（由申请人提供）： 幼年类风湿性关节炎 (JRA) 是最常见的儿童慢性疾病之一，影响着美国约 50,000 名儿童。JRA 的病因和发病机制很复杂，但显然存在遗传因素。主要组织相容性复合体的基因与 JRA 易感性之间的关联已得到充分确立，但尚未鉴定出因果遗传变异，更不用说用于改善临床实践的转化了。在过去的十年中，直接和间接证据表明激活的 T 细胞，特别是 Th1 表型在 JRA 发病机制中的作用。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会导致 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.测试所鉴定的遗传变异与JRA易感性和/或JRA的变量表达性之间的关联和联系。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 名患有 JRA 的同胞；(2) 500 名患有 JRA 的单身人士及其父母；(3) 从居住在 Intermountain West 的 650 多名 JRA 患者的登记中新确定的病例。提出了一项为期五年的指导计划，该计划将纳入教学和研究培训，并将由犹他大学的两位知名科学家进行指导。通过 NIH 资助的 K30 奖项，犹他大学综合临床研究中心提供了独特的临床研究教学培训计划，重点关注人类疾病的遗传基础。该计划包含对多用户核心设施、大学大型研究中心和大学医院指定单位等资源的访问，并为成熟的临床研究人员提供专门指导的深入研究经验。因此，犹他大学为最大限度地发挥本研究和申请人的潜力提供了理想的环境。