Blood Protein Markers of Biologic Treatment Response in Crohn's Disease

项目摘要 克罗恩病（CD）是一种胃肠道慢性炎症性疾病，通常并发于 肠瘘和狭窄，可导致不可逆的肠损伤。抗肿瘤坏死因子α （抗TNF）生物制剂在治疗CD中是有效的，但许多患者对抗TNF疗法没有应答。的 CD的治疗手段随着靶向新途径的新疗法而迅速增加，如抗- 白细胞介素12/23（抗IL 12/23）剂。迫切需要开发精准医学方法， 为个别CD患者选择正确的治疗方法。我们的小组已经在回肠中发现了一种新的细胞模块， 来自严重CD患者的手术切除组织称为IgG浆细胞，炎性单核细胞 吞噬细胞、活化T细胞和基质细胞（GIMATS）模块。我们已经证明， 在回肠活组织检查中具有高GIMATS富集的患者显著更可能抗TNF治疗失败。 然而，基于组织的生物标志物对于临床应用的可扩展性较低，而基于血液的标志物对于临床应用的可扩展性较低。 更容易实施和验证。最近，作为我的K23的一部分，我们证明了一个面板 在CD患者诊断时测定的外周血蛋白的浓度可以预测抗TNF治疗反应。 该血蛋白检测在两个独立队列中表现相似，可区分抗TNF 比单独的临床特征更好。我们的目标是通过扩大 作为抗TNF应答的潜在生物标志物测定的蛋白质。我们假设我们的表现 通过添加从发现组中选择的标志物，抗TNF血蛋白组将得到改善 富集了在与抗TNF抗性相关的细胞类型中高度表达的蛋白质（GIMATS模块）。在 目的1，我们建议评估一组扩展的血液蛋白质组学标记物与抗TNF 从免疫遗传学和免疫学的风险分层和识别中， 克罗恩病（RISK）儿童快速疾病进展的微生物标志物和海洋状态 克罗恩氏结肠炎地区登记（OSCCAR）队列。在目标2中，我们将探讨血液与 抗IL 12/23应答的蛋白质组学标志物，包括了解抗TNF应答的药物特异性 蛋白质组，在用抗IL 12/23疗法治疗的CD患者的两个前瞻性队列中。在这两个目标中，我们将 利用高度灵敏、稳健、可重复的蛋白质组学分析，该分析是样品保留的，具有很高的 可伸缩性通过R 03奖项产生的数据将作为未来R 01应用的基础， 扩大我们的蛋白质组发现工作，提高抗TNF抗体的血液蛋白质组的性能， 反应，并探索对一类新的生物制剂（抗IL 12/23治疗）的反应的血液标志物。

Project Summary Crohn’s disease (CD) is a chronic inflammatory condition of the gastrointestinal tract often complicated by intestinal fistulas and strictures that can result in irreversible bowel damage. Anti-tumor necrosis factor alpha (anti-TNF) biologics are efficacious in treating CD but many patients do not respond to anti-TNF therapy. The armamentarium for CD is rapidly increasing with new therapies that target novel pathways, such as anti- interleukin 12/23 (anti-IL12/23) agents. There is an urgent need to develop precision medicine approaches for selecting the right treatment for the individual CD patient. Our group has identified a novel cellular module in ileal surgical resection tissue from severe CD patients called the IgG plasma cells, Inflammatory Mononuclear phagocytes, Activated T cells, and Stromal cells (GIMATS) module. We have demonstrated that treatment naïve patients with high GIMATS enrichment in ileal biopsies are significantly more likely to fail anti-TNF therapy. However, tissue-based biomarkers are less scalable for clinical application, while blood-based markers will be more easily implemented and validated. More recently, in work as part of my K23, we demonstrated that a panel of peripheral blood proteins assayed at time of diagnosis in CD patients can predict anti-TNF treatment response. This blood protein panel performed similarly in two independent cohorts and could distinguish anti-TNF responders better than clinical features alone. We aim to build upon this prior work by expanding the number of proteins assayed as potential biomarkers of anti-TNF response. We hypothesize that the performance of our anti-TNF blood protein panel will improve through the addition of markers selected from a discovery panel enriched for proteins highly expressed in cell types associated with anti-TNF resistance (GIMATS module). In Aim 1, we propose to evaluate the association of an expanded panel of blood proteomic markers with anti-TNF response in anti-TNF treated CD patients from the Risk Stratification and Identification of Immunogenetic and Microbial Markers of Rapid Disease Progression in Children with Crohn’s Disease (RISK) and the Ocean State Crohn’s Colitis Area Registry (OSCCAR) cohorts. In Aim 2, we will then explore the association of blood proteomic markers with anti-IL12/23 response, including understanding the drug specificity of anti-TNF response protein panels, in two prospective cohorts of CD patients treated with anti-IL12/23 therapy. In both aims, we will utilize a highly sensitive, robust, replicable proteomics assay that is sample sparing with high potential for scalability. Data generated through this R03 award will serve as a foundation for future R01 applications by expanding our proteomic discovery efforts, improving the performance of blood protein panels of anti-TNF response, and exploring blood markers of response to a new class of biologic (anti-IL12/23 therapy).