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。 糖皮质激素的管理是治疗的主要手段之一。然而， 糖皮质激素是高度可变的，并且在其疾病是糖皮质激素依赖性的受影响个体中，副作用是常见的。该项目的总体目标是确定糖皮质激素直接影响的免疫应答途径的编码介质的基因变异是否影响IBD的易感性，以及受影响个体对 用糖皮质激素治疗。这一目标将通过（1）表征编码NF-κ B成员的16个候选基因中的每一个中的群体遗传变异模式， MAPK/JNK/AP-1和JAK/STAT信号传导网络，以及人糖皮质激素受体;以及 (2)检测这些候选基因的变异与IBD易感性和糖皮质激素治疗反应之间的关联。相关性研究将在2个不同的 队列：（1）552例所有年龄段的受影响IBD病例，包括约230对受影响同胞;和（2）315例儿科IBD三人组（受影响儿童加父母）。一个为期五年的指导计划，将结合教学和研究培训，并将在犹他州大学的一个完善的调查指导。通过NIH资助的K30奖，犹他州大学的综合临床研究中心提供了一个独特的临床研究培训计划，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，以及大学医院的指定临床研究单位-为成熟的临床研究者提供特定的指导密集研究经验。候选人将参加K30计划。因此，犹他州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.