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）： 少年类风湿关节炎（JRA）是影响美国大约50,000名儿童的最常见儿童的慢性疾病之一，尽管显然有遗传成分，但JRA的病因和发病机理很复杂。尽管鉴定了因果遗传变异的鉴定，但主要的组织相容性复合物和对JRA的易感性之间的关联尚未实现，但尚未实现改善临床实践的翻译。在过去的十年中，直接和间接的证据表明了活化的T细胞的作用，特别是Th1表型在JRA发病机理中的作用。该项目的目的是确定编码T细胞调节分子的基因的遗传变异是否有助于JRA易感性，发病机理和治疗结果的变化。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。测试识别与JRA的遗传变异与JRA的易感性和敏感性之间的关联和联系。这些研究将使用3种不同的人群进行，代表美国最大的JRA患者集合：（1）140个与JRA（2）500个与JRA及其父母的Singletons和（3）病例，以及（3）病例，从居住在West Intermountmountmountmountmountmountmountains Intermountain的注册表中。提出了一项为期五年的指导计划，该计划将纳入教学培训和研究培训，并由犹他大学的两名知名科学家指导。通过NIH资助的K30奖，犹他大学一般临床研究中心提供了一个独特的临床研究培训课程，重点是人类疾病的遗传基础。该计划结合了诸如多用户核心设施，大学的大型研究中心以及大学医院的指定单位等资源的访问权限，并为成熟的临床研究人员提供了特定的指导研究经验。因此，犹他大学为最大程度地提高了这项研究和该申请人的潜力提供了理想的环境。