Genetic basis of IBD susceptibility & steroid response

炎症性肠病是一种常见的慢性胃肠道疾病。 以腹痛、腹泻、生长障碍和全身不适为特征。 糖皮质激素的应用是治疗的主要方法之一。然而，这种药物的功效 糖皮质激素是高度可变的，其不良反应在疾病依赖糖皮质激素的患者中很常见。该项目的总体目标是确定编码直接受糖皮质激素影响的免疫反应途径的介体的基因变异是否会影响IBD的易感性，以及受影响的个体对 用糖皮质激素治疗。这一目标将通过(1)表征编码NF-ICB成员的16个候选基因中的每一个的群体遗传变异模式， MAPK/JNK/AP-1、JAK/STAT信号网络，以及人糖皮质激素受体； (2)检测这些候选基因变异与IBD易感性和糖皮质激素治疗反应之间的关联。关联研究将在两个不同的 队列：(1)所有年龄段的552例受影响的IBD病例，包括大约230对受影响的同胞；(2)315名儿童IBD三人组(受影响的儿童和父母)。一项为期五年的指导计划被提出，该计划将包括教学和研究培训，并将由犹他大学一位知名的研究人员指导。通过NIH资助的K30奖项，犹他大学的普通临床研究中心提供了一个独特的临床研究培训计划，专注于人类疾病的遗传基础。该计划结合了对资源的访问-例如多用户核心设施、大学的大型研究中心和大学医院的指定临床研究单位-以及为成熟的临床研究人员提供特定的有指导的密集研究经验。候选人将报名参加K30计划。因此，犹他大学为最大限度地发挥这项研究和候选人的潜力提供了一个理想的环境。

Inflammatory bowel disease (IBD) is a common, chronic disorder of the gastrointestinal tract characterized by abdominal pain, diarrhea, growth disturbances, and general discomfort. Administration of glucocorticoids is one of the mainstays of treatment. However, the efficacy of glucocorticoids is highly variable, and adverse effects are common in affected individuals whose disease is glucocorticoid-dependent. The overall goal of this project is to determine whether variants in genes encoding mediators of immune response pathways directly affected by glucocorticoids influence susceptibility to IBD, as well as an affected individual's response to treatment with glucocorticoids. This goal will be accomplished by (1) characterizing the pattern of population genetic variation in each of 16 candidate genes encoding members of the NF-icB, MAPK/JNK/AP-1, and JAK/STAT signaling networks, and the human glucocorticoid receptor; and (2) testing for association between variants in these candidate genes and susceptibility to IBD and therapeutic response to glucocorticoids. Association studies will be performed in 2 different cohorts: (1) 552 affected-IBD cases of all ages including approximately 230 affected sib-pairs; and (2) 315 pediatric IBD trios (affected child plus parents). A five year mentored program is proposed that will incorporate both didactic and research training and will be guided by a well-established investigator at the University of Utah. Through an NIH-funded K30 award, the University of Utah's General Clinical Research Center provides a unique training program in clinical research focused on the inherited basis of human disease. This program incorporates access to resources-such as multiuser core facilities, large research centers at the University, and a designated clinical research unit in the University Hospital- with a specific mentored intensive research experience for maturing clinical investigators. The candidate will enroll in the K30 program. Thus the University of Utah provides an ideal environment for maximizing the potential of this study and the candidate.