Mechanisms and Markers of Small Intestinal Epithelial Injury and Villous Atrophy

小肠上皮损伤和绒毛萎缩的机制和标志物

• 批准号: 10362564
• 负责人: Jocelyn Anne Silvester
• 金额: $ 19.32万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-07 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10362564
• 关键词: Address; Adult; Advisory Committees; Affect; Angiotensin II Receptor; Antibodies; Architecture; Autoimmune; Award; Basic Science; Bioinformatics; Biological Markers; Biology; Biopsy; Biopsy Specimen; Blood specimen; Boston; Celiac Disease; Cells; Characteristics; Clinical; Clinical Research; Clinical Trials; Cohort Studies; Data; Diagnosis; Discipline; Disease; Doctor of Philosophy; Ensure; Enterocytes; Etiology; Experimental Designs; Food; Foundations; Functional disorder; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genes; Genetic; Gluten; Gluten-free diet; Goals; Grant; Histology; Immune system; Immunologic Factors; Immunology; Individual; Intestines; K-Series Research Career Programs; Knowledge; Manitoba; Medical; Mentors; Messenger RNA; Modeling; Molecular; Molecular Profiling; Monitor; Mucous Membrane; Natural regeneration; Participant; Pathway interactions; Patient Monitoring; Patient-Focused Outcomes; Patients; Pediatric Hospitals; Permeability; Persons; Pharmaceutical Preparations; Physicians; Protocols documentation; Regression Analysis; Research; Resources; Scientist; Small Intestines; Structure; Surface; Techniques; Therapeutic; Time; Time Study; Tissues; Toxic effect; Training; Transcript; Treatment outcome; Villous; Villous Atrophy; Work; Writing; base; career; clinical practice; clinically relevant; clinically significant; cohort; comparative; diagnostic biomarker; differential expression; disease diagnosis; epithelial injury; experience; follow-up; functional genomics; genomic data; gut inflammation; improved; insight; instructor; intestinal epithelium; intestinal injury; light microscopy; medical schools; microbiota; novel; olmesartan; patient oriented research; peripheral blood; programs; response; response to injury; skills; specific biomarkers; statistics; therapeutic target; tool; transcriptome sequencing; transcriptomics; treatment response

PROJECT SUMMARY Mucosal remodeling with villous atrophy is a generic response to small intestinal injury with many causes that require different treatments. While easily recognized on intestinal biopsy specimens, determining the specific cause of villous atrophy is more challenging and often leads to therapeutic delays. This Career Development Award is based upon the hypothesis that transcriptomics can both elucidate mechanisms of villous atrophy across diseases and provide improved tools for diagnosis and monitoring. Jocelyn A. Silvester, MD PhD is Instructor at Harvard Medical School and a subspecialist within the Celiac Disease Program at Boston Children's Hospital. She has gained substantial basic and clinical research experience during her doctoral and medical training and has demonstrated commitment to an academic career in patient oriented research. This Career Development Award will provide additional mentored training and research opportunities in bioinformatics and mucosal immunology for Dr Silvester to advance her quantitative research skills while addressing the current knowledge gap related to mechanisms of small intestinal epithelial injury and the lack of disease-specific biomarkers of villous atrophy. Dr Ciarán Kelly, an acknowledged expert in celiac disease and intestinal inflammation, and Dr Isaac Kohane, an expert in bioinformatics and quantitative biology, will serve as mentors. In addition an Advisory Committee comprised of experts across multiple relevant disciplines (Drs Leffler, Lencer, Goldsmith, and Fasano) will meet with the applicant and mentors regularly to assess progress. This award will aid Dr Silvester in establishing an independent research program as an academic physician- scientist through a structured training plan that includes formal course work in bioinformatics and statistics, as well as relevant clinical research in functional genomics. She will also receive additional training in quantitative interpretation of intestinal histology and grant writing to facilitate her goal of using insights from large-scale genomic data to improve diagnosis, treatment, and outcomes for patients with celiac disease and other enteropathies. The research at the foundation of this application aims to characterize the different mechanisms leading to villous atrophy and to identify a molecular signature of celiac disease activity in peripheral blood. Celiac disease will be used as a model to study the time course of changes occurring as villous atrophy recurs during gluten challenge in celiac patients who had recovered on a gluten-free diet. Additionally, comparative transcriptomic studies will be performed using intestinal tissue from patients with celiac disease, adult-onset autoimmune enteropathy and drug-induced (olmesartan) enteropathy. Finally, we will study peripheral blood mRNA markers of villous atrophy in participants in our ongoing Manitoba Celiac Disease Cohort study undergoing protocol biopsy 24 months after starting a gluten-free diet. The substantial research, educational and clinical resources of Boston Children's Hospital, Harvard Medical School and the Harvard Celiac Research Program are committed to the applicant to ensure successful attainment of the goals of this award.

项目摘要 用绒毛萎缩进行粘膜重塑是对小损伤的一般反应，许多原因是 需要不同的治疗方法。 绒毛萎缩的原因是具有挑战性的，通常会导致治疗性延迟 奖项基于该转录组学可以既可以质萎缩症 跨疾病，提供改进的诊断和监测工具。 哈佛医学院的讲师和波士顿腹腔疾病计划中的专科医生 儿童医院。 医学培训，并表现出对以患者为导向研究的学术生涯的承诺。 这项职业发展奖将威尔·威尔·威尔·威尔·威尔·培训和 Silvance博士的生物信息学和粘膜免疫学，以提高其定量研究技能，同时 解决与小型肠道主义官方机制有关的当前知识差距，缺乏 绒毛性萎缩的疾病特异性生物标志物。 肠道炎症和生物信息学和定量生物学专家艾萨克·科万（Isaac Kohane）将作为 导师。 Leffler，Lencer，Goldsmith和Fasano）将定期与申请人和导师会面，以评估进度。 该奖项将有助于西尔维斯特博士作为学术医师建立一项注册的研究计划 - 科学家通过一个结构化培训计划，其中包括生物信息学和统计学的正式课程工作， 以及功能基因组学方面的相关临床研究。 肠道组织学和赠款写作的解释，以促进她使用大规模见解的目标 基因组数据以改善腹腔疾病和其他患者的诊断，治疗和结果 肠道疾病。 导致绒毛性萎缩，并确定外周血中乳糜泻活性的分子特征。 腹腔疾病将用作研究随着绒毛萎缩复发的时间变化的时间过程的模型 在面筋挑战期间，在无麸质饮食中恢复的腹腔患者 使用腹腔疾病患者，成人核心患者的肠道组织进行转录组学研究 自身免疫性肠病和药物诱导的肠道疾病。 我们正在进行的曼尼托巴氏乳糜型疾病队列研究中参与者的绒毛萎缩的mRNA标记 开始无麸质饮食后24个月进行调节活检。 波士顿儿童医院，哈佛医学院和哈佛腹腔研究的临床资源 计划致力于申请人，以确保成功实现该奖项的目标。