Paneth cell phenotype as a predictive biomarker for ulcerative colitis

潘氏细胞表型作为溃疡性结肠炎的预测生物标志物

• 批准号: 10455588
• 负责人: Ta-Chiang Liu
• 金额: $ 36.16万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-24 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10455588
• 关键词: Affect; Anastomosis - action; Anus; Biological Markers; Caring; Cell physiology; Cellular Morphology; Chronic; Classification; Clinical; Clinical Trials; Colectomy; Complex; Cost Measures; Crohn' s disease; Data; Development; Disease; Disease Management; Disease remission; Economic Burden; Epithelial Cells; Excision; Genetic Markers; Genetic Predisposition to Disease; Goals; Grant; Ileal Reservoirs; Image; Inflammatory; Inflammatory Bowel Diseases; Interobserver Variability; Longterm Follow-up; Manuals; Medical Genetics; Medical center; Methods; Molecular; Molecular Target; Monitor; Morphology; Mucous Membrane; Natural History; Natural Immunity; Observer Variation; Operative Surgical Procedures; Paneth Cells; Pathologist; Pathology; Pathway interactions; Patients; Phenotype; Positioning Attribute; Postoperative Period; Pouchitis; Prevalence; Process; Prognosis; Prognostic Marker; Public Health; Reproducibility; Research; Research Personnel; Role; Sampling; Serum; Serum Markers; Small Intestines; Specimen; Standardization; Subgroup; Surgical Pathology; Testing; Therapeutic; Time; Tissues; Translating; Ulcerative Colitis; Universities; Washington; Work; aggressive therapy; analysis pipeline; base; cell type; clinical practice; clinically relevant; cohort; combinatorial; deep learning; deep learning algorithm; dysbiosis; experience; experimental study; gastrointestinal; gene environment interaction; genetic association; gut homeostasis; improved; innate immune function; innovation; insight; intestinal epithelium; novel; novel strategies; outcome prediction; patient stratification; personalized medicine; phenotypic biomarker; predictive marker; prognostic; treatment strategy

ABSTRACT One of the challenges for the management of ulcerative colitis (UC; a subtype of inflammatory bowel disease) is the lacking of a predictive biomarker that can help stratify patients for personalized treatment strategies. We have previously shown that in Crohn’s disease (CD; another subtype of inflammatory bowel disease), the morphologic phenotype of small intestinal Paneth cells readily predicts outcome in post-surgical CD patients. Given the shared genetic etiology and clinical features between CD and UC, we hypothesize that Paneth cell phenotype will also predict outcome in UC. Our long-term goal is to define the clinical indications of inflammatory bowel disease of which Paneth cell phenotype can predict outcome. The objective of this grant is to determine to the extent of which Paneth cell phenotype predicts development of ileal complications in UC. The central hypothesis is that in UC patients undergoing total colectomy and ileal pouch anal anastomosis (IPAA), the Paneth cell phenotype obtained at time of colectomy will predict development of pouchitis and de novo CD in the ileal pouch. Our rationale is that Paneth cell phenotype will offer better outcome prediction over current practice. Our specific aims will test the following hypotheses: (Aim1) Paneth cell phenotype correlates with ileal complications in UC patients with IPAA; (Aim 2) Deep learning will reduce observer variation and enhance rigor and reproducibility of Paneth cell phenotype analysis in surgical pathology specimens, and also identify novel clinical factors that correlate with Paneth cell function; (Aim 3) Serum markers that correlate with Paneth cell phenotype could be used to predict outcome in UC. Upon conclusion, we will understand the role for Paneth cell function in modulating disease course in IBD. This contribution is significant since it will establish Paneth cell phenotype as a critical predictive biomarker for IBD. The proposed research is innovative because we use state-of-the-art deep learning approach to build an imaging analysis pipeline, and to identify novel clinical factors that affect Paneth cell functions. Identifying how epithelial cells with innate immune function affect disease course will provide insight into other inflammatory disorders.

摘要 溃疡性结肠炎(UC；炎症性肠病的一种亚型)治疗面临的挑战之一 缺乏一个预测性的生物标记物，可以帮助患者进行个性化治疗策略的分层。我们 先前的研究表明，在克罗恩病(CD；炎症性肠病的另一种亚型)中， 小肠Paneth细胞的形态表型很容易预测CD术后患者的预后。 鉴于CD和UC具有相同的遗传病因和临床特征，我们假设潘氏细胞 表型也可以预测UC的预后。我们的长期目标是明确临床适应症 潘氏细胞表型可预测预后的炎症性肠病。这笔赠款的目的是 目的：确定潘氏细胞表型在多大程度上预测UC回肠并发症的发生。 中心假设是在接受全结肠切除和回肠储袋肛门吻合术的UC患者中 (IPAA)，结肠切除时获得的Paneth细胞表型将预测膀胱炎和De的发展 回肠袋里的Novo CD。我们的理论基础是潘氏细胞表型将提供更好的预后预测 目前的做法。我们的具体目标将检验以下假设：(Aim1)Paneth细胞表型与 (目标2)深度学习将减少观察者的差异和 提高外科病理标本中潘氏细胞表型分析的严密性和重复性，还 确定与潘氏细胞功能相关的新的临床因素；(目标3)与以下各项相关的血清标志物 Paneth细胞表型可用来预测UC的预后。在总结的时候，我们就会理解这个角色 探讨潘氏细胞在调节IBD病程中的作用。这一贡献意义重大，因为它将 建立Paneth细胞表型作为IBD的关键预测生物标志物。建议的研究具有创新性。 因为我们使用最先进的深度学习方法来构建成像分析管道，并识别 影响潘氏细胞功能的新临床因素。鉴定具有先天免疫功能的上皮细胞 功能影响疾病的病程将提供对其他炎症性疾病的洞察。