GENETIC BASIS OF IBD SUSCEPTIBILITY AND STEROID RESPONSE

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 来自动物模型和人类研究的实验数据表明，1）肿瘤坏死因子α（TNF α），2）Th 1/Th 2细胞因子应答，和3）活化的淋巴细胞对凋亡的抗性在肠易激疾病（IBD）的发病机制中起重要作用。有效的TNF α信号传导、Th 1/Th 2淋巴细胞分化和活化的淋巴细胞对凋亡的抵抗需要NF-κ B、MAPK/JNK/AP-1和JAK/STAT信号传导网络，并且实验证据表明糖皮质激素直接影响这些通路。我们假设编码这些信号网络的关键介质的基因的变异与IBD的易感性和糖皮质激素的治疗反应有关。为了解决这一假设，我们提出以下具体目标： 1.1.表征编码人糖皮质激素受体的基因以及NF-κ B、MAPK/JNK/AP-1和JAK/STAT信号网络成员的多样性。 1.2检测候选基因中遗传变异与IBD易感性之间的关联。 1.3. IBD患者中候选多态性与糖皮质激素反应之间的相关性检测。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Experimental data from both animal models and studies in humans demonstrate that 1) tumor necrosis factor alpha (TNFalpha), 2) the Th1/Th2 cytokine response, and 3) the resistance of activated lymphocytes to apoptosis play important roles in the pathogenesis of irritable bowel disease (IBD). Effective TNFalpha signaling, Th1/Th2 lymphocyte differentiation, and the resistance of activated lymphocytes to apoptosis require the NF-kappaB, MAPK/JNK/AP-1, and JAK/STAT signaling networks, and experimental evidence suggests that glucocorticoids directly influence these pathways. We hypothesize that variation in the genes encoding the pivotal mediators of these signaling networks are associated with susceptibility to IBD and therapeutic response to glucocorticoids. To address this hypothesis, we propose the following specific aims: 1.1. Characterize diversity in genes encoding the human glucocorticoid receptor, and members of the NF-kapppaB, MAPK/JNK/AP-1, and JAK/STAT signaling networks. 1.2 Test for association between genetic variants in candidate genes and susceptibility to IBD. 1.3. Test for association between candidate polymorphisms and the response to glucocorticoids in patients with IBD.