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

项目摘要 克罗恩病(CD)是一种慢性胃肠道炎症性疾病，常并发 可导致不可逆的肠道损伤的肠瘘和狭窄。抗肿瘤坏死因子α (抗肿瘤坏死因子)生物制剂治疗CD有效，但许多患者对抗肿瘤坏死因子治疗无效。这个 随着针对新途径的新疗法的出现，CD的治疗手段正在迅速增加，例如抗 白介素12/23(抗白介素12/23)制剂。迫切需要开发精准医学方法来治疗 为个别CD患者选择正确的治疗方法。我们的团队在回肠中发现了一种新的细胞模块 重症CD患者手术切除组织中的免疫球蛋白G浆细胞，炎性单核细胞 吞噬细胞、激活的T细胞和基质细胞(GIMATS)模块。我们已经证明了这种治疗是幼稚的 回肠活检中GIMATS丰度高的患者抗肿瘤坏死因子治疗失败的可能性显著增加。 然而，基于组织的生物标记物在临床应用的可扩展性较差，而基于血液的标记物将 更易于实施和验证。最近，在作为我K23的一部分的工作中，我们展示了一个小组 CD患者确诊时检测外周血蛋白水平可预测抗肿瘤坏死因子治疗反应。 这个血液蛋白质组在两个独立的队列中表现相似，可以区分抗肿瘤坏死因子 应答者比仅有临床特征的人更好。我们的目标是在先前工作的基础上，扩大 蛋白质被检测为潜在的抗肿瘤坏死因子反应的生物标志物。我们假设我们的表现 通过增加从发现小组中选择的标志物，抗肿瘤坏死因子血液蛋白小组将得到改善 富含与抗肿瘤坏死因子抵抗相关的细胞类型中高表达的蛋白质(GIMATS模块)。在……里面 目的1，我们建议评估一组扩大的血液蛋白质组标志物与抗肿瘤坏死因子的相关性。 抗肿瘤坏死因子治疗CD患者应答的危险分层及免疫遗传和免疫功能鉴定 克罗恩病(Risk)和海洋状态儿童疾病快速进展的微生物标志物 克罗恩结肠炎地区登记处(OSCCAR)队列。在目标2中，我们将探索血液与 抗IL 12/23反应的蛋白质组标志物，包括了解抗肿瘤坏死因子反应的药物特异性 蛋白质板，在两个接受抗IL12/23治疗的CD患者的前瞻性队列中。在这两个目标中，我们将 利用一种高度敏感、可靠、可复制的蛋白质组学分析方法，该方法节省样本，具有很高的潜在应用价值 可扩展性。通过此R03奖项生成的数据将作为未来R01应用程序的基础 扩大我们的蛋白质组发现工作，提高抗肿瘤坏死因子的血液蛋白质板的性能 反应，并探索对一类新的生物(抗IL12/23治疗)反应的血液标记物。

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).