Characterizing the Biologic Evolution of Crohn's Disease Like Pouch Inflammation in Ulcerative Colitis Patients After Restorative Proctocolectomy with Ileal Pouch Anal Anastomosis

描述溃疡性结肠炎患者行回肠储袋肛门吻合术恢复性直肠结肠切除术后克罗恩病样储袋炎症的生物学演变

• 批准号: 10558701
• 负责人: Maia Kayal
• 金额: $ 19.09万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10558701
• 关键词: 16S ribosomal RNA sequencing; Affect; American; Anastomosis - action; Antibiotics; Anus; Anxiety; Automobile Driving; Biological; Childhood; Chronic; Clinical; Cohort Analysis; Colectomy; Colitis; Colon; Country; Crohn' s disease; Data; Defecation; Development; Diagnostic; Disease; Disease Marker; Disease model; Distal; Environment; Evolution; Excision; Exposure to; Faculty; Failure; Faith; Feces; Formalin; Funding; Gastroenterology; Gastrointestinal tract structure; Genes; Genetic; Genetic Anticipation; Genetic Risk; Genome; Goals; Grant; Histologic; Hospitals; Ileal Reservoirs; Inflammation; Inflammatory Bowel Diseases; Intention; Intestines; Link; Longitudinal cohort; Medical; Medicine; Mental Depression; Mentorship; Methodology; Modeling; Nature; Operative Surgical Procedures; Ostomy; Outcome; Paraffin Embedding; Pathway interactions; Patients; Pediatrics; Pelvis; Play; Procedures; Rectum; Refractory; Reporting; Research; Research Personnel; Restorative Proctocolectomy; Risk; Role; Sampling; Secondary to; Stomas; Symptoms; Testing; Therapeutic; Time; Tissue Sample; Training; Ulcerative Colitis; Uncertainty; United States National Institutes of Health; Work; biobank; career; clinical application; clinical care; cohort; differential expression; experience; genetic variant; genome sciences; genomic locus; genotyped patients; gut inflammation; host microbiome; ileum; innovation; medical schools; metabolome; metabolomics; microbial; microbiome; microbiome analysis; microbiota; mid-career faculty; multidisciplinary; news; pathobiont; patient oriented; personalized medicine; pre-clinical; preservation; prevent; professor; profiles in patients; prognostication; prospective; psychosocial; rectal; restoration; risk stratification; skill acquisition; skills; therapeutic target; transcriptome; transcriptome sequencing; transcriptomics; translational genetics; translational scientist

This project will characterize the genetic variants, ileal transcriptome, microbial and metabolomic profiles in patients with medically refractory ulcerative colitis (UC) who require restorative proctocolectomy (RPC) with ileal pouch anal anastomosis (IPAA) and subsequently develop Crohn’s Disease-like pouch inflammation (CDLPI). The goal is to identify the at risk -omic features associated with CDLPI. Candidate: The primary objective of this application is to support Dr. Maia Kayal’s development into an independent, patient-oriented translational investigator in the field of inflammatory bowel disease (IBD). Dr. Kayal’s career goal is to become an independent researcher with expertise in the integration of analytic methodologies to answer high-impact clinical questions in the field of IBD. To achieve this goal, Dr. Kayal has devised a training plan that is focused on the development of skills in: 1) longitudinal cohort analysis, 2) biological interpretation of transcriptome analysis, 3) clinical application of microbiome and metabolome analysis, and 4) clinical incorporation of statistical genetics. She has assembled a powerful multidisciplinary mentorship team at the Icahn School of Medicine at Mount Sinai (ISMMS) with (1) Dr. Marla Dubinsky, Professor of Medicine and Pediatrics, Chief of Pediatric Gastroenterology, and Co-Director of the Feinstein IBD Center, (2) Dr. Judy Cho, Professor and Dean of Translational Genetics, Director of the Institute for Personalized Medicine, and (3) Dr. Jeremiah Faith, Associate Professor in the Department of Genetics and Genomic Sciences and Faculty Director of the Microbiome Translational Center. Environment: The ISMMS 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 for research and clinical care. Research: Up to 30% of patients with treatment refractory UC will require surgery, the most common of which is the RPC with IPAA. This continence preserving procedure involves the removal of the colon and rectum, construction of a pouch from ileum to serve as an internal pelvic reservoir for stool, and restoration of intestinal continuity. Approximately 20% of patients develop CDLPI within two years of their final surgical stage, and up to 50% of these patients do not respond to standard IBD therapies and require surgical pouch removal and the creation of a permanent ostomy. To date, there is no way to predict before colon removal which patient with UC will develop CDLPI and pouch failure. We propose to characterize the genetic variants, ileal transcriptome, microbial and metabolomic profiles associated with CDLPI in patients with UC who undergo RPC with IPAA. We hypothesize that patients who develop CDLPI harbor distinctive at risk genetic and ileal transcriptomic features present at the time of colectomy before pouch creation, and that CDLPI is triggered over time by exposure to specific microbiota.

该项目将描述遗传变异，回肠转录组，微生物和代谢组学特征， 需要回肠修复性直肠结肠切除术（RPC）的难治性溃疡性结肠炎（UC）患者 袋肛门吻合术（IPAA），并随后发展克罗恩病样袋炎症（CDLPI）。 目的是确定与CDLPI相关的风险组学特征。 候选人：该应用程序的主要目标是支持马亚·卡亚尔博士发展成为 炎症性肠道疾病（IBD）领域独立、以患者为导向的转化研究者。博士 Kayal的职业目标是成为一名独立的研究人员，在分析整合方面拥有专业知识。 这些方法可以回答IBD领域的高影响力临床问题。为了实现这一目标，Kayal博士 设计了一个培训计划，重点是技能的发展：1）纵向队列分析，2）生物 转录组分析的解释，3）微生物组和代谢组分析的临床应用，以及4） 统计遗传学的临床整合。她组建了一个强大的多学科导师团队， 西奈山伊坎医学院（ISMMS）与（1）医学教授Marla Dubinsky博士和 儿科，儿科胃肠病学主任，Feinstein IBD中心联合主任，（2）Judy Cho博士， 教授和翻译遗传学系主任，个性化医学研究所所长，和（3）博士。 Jeremiah Faith，遗传学和基因组科学系副教授兼系主任 微生物组翻译中心 环境：ISMMS拥有优秀研究的悠久传统，是前20名医学院之一。 在NIH的资助下。西奈山消化科一直被认为是前10名之一， 美国新闻和世界报道在该国的研究和临床护理部门。 研究：高达30%的难治性UC患者需要手术，其中最常见的是 RPC与IPAA这种保留直肠的手术包括切除结肠和直肠， 从回肠构建一个袋，作为粪便的内部骨盆储存器，并恢复肠 连续性大约20%的患者在其最终手术阶段的两年内发生CDLPI，并且高达 这些患者中有50%对标准IBD疗法没有反应，需要手术切除囊袋， 形成永久性的造口。迄今为止，在结肠切除之前无法预测哪位UC患者 将发生CDLPI和包装袋失效。我们建议对基因变异，回肠转录组， 接受IPAA RPC的UC患者中与CDLPI相关的微生物和代谢组学特征。我们 假设发生CDLPI的患者具有独特的高危遗传和回肠转录组学特征 存在于结肠切除术时，在袋创建之前，并且CDLPI随着时间的推移通过暴露于 特定的微生物群