STAT5 variants in the pathogenesis of inflammatory bowel disease

STAT5变异在炎症性肠病发病机制中的作用

• 批准号: 511537322
• 负责人: Professor Dr. Sebastian Zeissig
• 金额: --
• 依托单位: Medizinische Klinik und Poliklinik I
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/511537322?language=en
• 关键词: STAT5; variants; pathogenesis; inflammatory; bowel

Inflammatory bowel disease (IBD), with its two main entities Crohn's disease and ulcerative colitis, results from a complex interplay of genetic and environmental factors. Genetic analyses revealed IBD-associated polymorphisms in more than 200 genetic loci. However, the mechanisms which link individual genes and polymorphisms to IBD are still poorly understood. The identification of monogenic forms of IBD in which the loss of individual genes is associated with IBD, has tremendously contributed to our understanding of genetic pathways to IBD. Specifically, this work has revealed vastly different pathways to IBD based on defects in the intestinal epithelium, innate immunity or adaptive immunity. Moreover, these studies have highlighted new avenues to personalized treatment of IBD. The screening for known or novel monogenic forms of IBD has become an important aspect of clinical diagnostics, particularly for pediatric and familial forms of IBD. Through such diagnostics, we could recently identify a missense variant in signal transducer and activator of transcription (STAT) 5A (STAT5A E518K) in a female patient with severe, early-onset Crohn's disease. STAT5A is a transcription factor with important roles in immunity, but variants in STAT5A have so far not been linked to monogenic forms of IBD. Functional investigations demonstrated that STAT5A E518K was associated with reduced STAT5A expression and function. To investigate its function in vivo, we capitalized on conservation of the STAT5A E518 residue and its flanking region in mice and engineered mice carrying this variant in the endogenous Stat5a locus. We could demonstrate that STAT5A E518K is associated with defects in immunity and promotes susceptibility to chemically induced colitis. Based on these preliminary data, we aim to characterize the role of this and other STAT5 variants in the pathogenesis of IBD. Specifically, we will (i) investigate whether STAT5A E518K is associated with alterations in intestinal epithelial function or mucosal immunity in mice and in the patient carrying STAT5A E518K; (ii) study whether mice carrying STAT5A E518K exhibit susceptibility to chemical, immunological, and microbial triggers of intestinal inflammation; and (iii) investigate the roles of other STAT5A and STAT5B variants in the pathogenesis of IBD. Together, this work will characterize STAT5 variants as a potential monogenic origin of IBD and shall identify the pathways that link STAT5 to IBD.

炎症性肠病（IBD），其两个主要实体克罗恩病和溃疡性结肠炎，是遗传和环境因素复杂相互作用的结果。遗传分析显示IBD相关的多态性在200多个遗传位点。然而，将个体基因和多态性与IBD联系起来的机制仍然知之甚少。IBD的单基因形式的鉴定，其中单个基因的丢失与IBD相关，极大地促进了我们对IBD遗传途径的理解。具体来说，这项工作揭示了基于肠上皮缺陷，先天免疫或适应性免疫的IBD的不同途径。此外，这些研究强调了IBD个性化治疗的新途径。筛选已知或新的单基因形式的IBD已成为临床诊断的重要方面，特别是对于IBD的儿科和家族形式。通过这样的诊断，我们最近可以确定一个错义变异信号转导和转录激活因子（STAT）5A（STAT5A E518K）的严重，早发性克罗恩病的女性患者。STAT5A是在免疫中具有重要作用的转录因子，但STAT5A的变体迄今为止尚未与IBD的单基因形式相关联。功能研究表明，STAT5A E518 K与STAT5A表达和功能降低相关。为了研究其在体内的功能，我们利用了小鼠中STAT5A E518残基及其侧翼区的保守性，以及在内源性Stat5a基因座中携带该变体的工程小鼠。我们可以证明STAT5A E518K与免疫缺陷相关，并促进对化学诱导的结肠炎的易感性。基于这些初步数据，我们的目标是表征这种和其他STAT5变体在IBD发病机制中的作用。具体而言，我们将（i）研究STAT5A E518 K是否与小鼠和携带STAT5A E518 K的患者的肠上皮功能或粘膜免疫的改变相关;（ii）研究携带STAT5A E518 K的小鼠是否表现出对肠道炎症的化学、免疫和微生物触发剂的易感性;和（iii）研究其它STAT5A和STAT5B变体在IBD发病机制中的作用。总之，这项工作将表征STAT5变体作为IBD的潜在单基因起源，并将确定将STAT5与IBD联系起来的途径。