Assessing Predictors of Response to Anti-Tumor Necrosis Alpha Therapy in Early Crohns Disease

该项目将评估对抗肿瘤坏死因子α(anti-TNF)反应的预测生物标记物。 早期克罗恩病(CD)患者的治疗。应聘者：此应用程序的主要目标是 支持Ryan Ungaro博士的职业发展，成为一名独立的、以患者为导向的研究人员 炎症性肠病(IBD)患者的个性化药物。昂加罗博士的职业目标是成为 在应用预测性生物标志物和模型以选择最佳生物标志物方面的独立研究人员和领导者 对新近确诊的IBD患者进行治疗和优化护理。昂加罗博士提议的培训活动包括 在四个领域：1)高级生物统计分析，2)预测生物标记物分析，3)计算基因组学， (4)免疫监测原理。为了实现这一目标，他组建了一个由他领导的指导和咨询团队 作者朱迪·赵博士，查尔斯·布朗夫曼个性化医学研究所所长， 翻译基因组学，以及消化内科主任布鲁斯·桑兹博士，他拥有 IBD疗法的临床和翻译研究，推动了许多开创性的研究 反跨国公司。环境：位于西奈山的伊坎医学院有着优秀的传统 是美国国立卫生研究院资助的前20所医学院之一。西奈山分部 胃肠病学一直被《美国新闻与世界报》评为美国十大科室之一 他是IBD研究和临床护理领域的国际领先者。研究：CD是一种慢性疾病， 进行性炎症影响胃肠道的进行性发炎状态。抗肿瘤坏死因子药物在很大程度上 改善了CD患者的治疗，但有相当数量的人对这些没有反应 这些药物非常昂贵，而且具有潜在的致命副作用。治疗CD的新药物类别是 被释放为个性化医疗带来了机遇。临床医生将需要这些工具来帮助决定 哪种药物对每个CD患者最有效。这一点在最近几年将特别重要 对确诊的患者进行有效的早期治疗可减少远期并发症。因此我们的 具体目的是：(1)确定外周血蛋白质组标志物与抗-HBs应答的相关性。 肿瘤坏死因子(2)评估肠道组织基因表达标志与抗肿瘤坏死因子应答的关系 探讨单细胞RNA的黏膜免疫构筑及其对抗肿瘤坏死因子应答的预测能力 肠道活检组织的测序(ScRNASeq)。我们将研究最近确诊的CD患者(在两年内 诊断)来自3个有生物样本的前瞻性队列：一个基于人群的IBD初始队列，一个多中心 最近诊断的儿童CD患者的队列，以及与以下链接的IBD患者的单中心生物信息库 健康记录数据。此外，还将招募一批最近确诊的CD患者进行scRNASeq 分析。在颁奖期间开发的一般方法和技能也可以应用于新的目标 并为未来对IBD早期治疗反应的生物标志物的研究奠定了基础。

This project will evaluate predictive biomarkers of response to anti-tumor necrosis factor alpha (anti-TNF) therapy in early Crohn's disease (CD) patients. Candidate: The primary objective of this application is to support Dr. Ryan Ungaro's career development into an independent patient-oriented investigator in the field of personalized medicine for inflammatory bowel disease (IBD) patients. Dr. Ungaro's career goal is to become an independent researcher and leader in the application of predictive biomarkers and models to select the best treatment and optimize care for recently diagnosed IBD patients. Dr. Ungaro's proposed training activities are in four areas: 1) advanced biostatistical analysis, 2) predictive biomarker analysis, 3) computational genomics, and 4) principles of immune monitoring. To achieve this, he has assembled a mentoring and advisory team led by Dr. Judy Cho, Director of the Charles Bronfman Institute of Personalized Medicine and an expert in translational genomics, and Dr. Bruce Sands, Chief of the Division of Gastroenterology, who has expertise in clinical and translational investigation of IBD therapeutics, having driven much of the pioneering research in anti-TNFs. Environment: The Icahn School of Medicine at Mount Sinai has a strong tradition of outstanding research and is one of the top 20 medical schools in NIH funding. The Mount Sinai Division of Gastroenterology is consistently considered one of the top 10 divisions in the country by US News and World Report and is an international leader in IBD research and clinical care. Research: CD is a chronic, progressive, inflammatory condition affecting the gastrointestinal tract. Anti-TNF medications have vastly improved the treatment of CD patients, however a significant number of individuals do not respond to these agents which are very costly and have potentially fatal side effects. New classes of medications for CD are being released bringing the opportunity for personalized medicine. Clinicians will need the tools to help decide which medication will work best for each individual CD patient. This will be particularly important in recently diagnosed patients since effective early treatment can decrease long-term complications. Therefore our specific aims are to (1) determine the association of peripheral blood proteomic markers with response to anti- TNF (2) assess the association of intestinal tissue gene expression markers with anti-TNF response and (3) explore the mucosal immune architecture and predictive capacity for anti-TNF response of single cell RNA sequencing (scRNASeq) of intestinal biopsies. We will study recently diagnosed CD patients (within 2 years of diagnosis) from 3 prospective cohorts with biosamples: a population-based IBD inception cohort, a multi-center cohort of recently diagnosed pediatric CD patients, and a single-center biorepository of IBD patients linked to health records data. In addition, a cohort of recently diagnosed CD patients will be recruited for scRNASeq analysis. The general approaches and skills developed during this award can also be applied to new targeted medications and form the basis for future research on biomarkers of treatment response in early IBD.