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: 10371673
• 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/10371673
• 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; Feces; Formalin; Funding; Gastroenterology; Gastrointestinal tract structure; Genes; Genetic; Genetic Risk; Genome; Goals; Grant; Histologic; Hospitals; Ileal Reservoirs; Inflammation; Inflammatory Bowel Diseases; Institutes; 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; restoration; risk stratification; skill acquisition; skills; surgical risk; 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.

该项目将表征遗传变异、回肠转录组、微生物和代谢组学特征 需要进行回肠恢复性直肠结肠切除术 (RPC) 的难治性溃疡性结肠炎 (UC) 患者 储袋肛门吻合术 (IPAA)，随后出现克罗恩病样储袋炎症 (CDLPI)。 目标是识别与 CDLPI 相关的风险组学特征。 候选人：此应用程序的主要目标是支持 Maia Kayal 博士发展成为一名 炎症性肠病 (IBD) 领域独立、以患者为导向的转化研究者。 Kayal 的职业目标是成为一名独立研究员，拥有分析整合方面的专业知识 为了实现这一目标，Kayal 博士制定了解决 IBD 领域高影响力临床问题的方法。 制定了一项培训计划，重点关注以下方面的技能发展：1）纵向队列分析，2）生物学 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) 她在统计遗传学的临床结合中组建了一支强大的多学科指导团队。 西奈山伊坎医学院 (ISMMS) 的 (1) Marla Dubinsky 博士，医学教授 儿科、儿科胃肠病学主任兼 Feinstein IBD 中心联席主任，(2) Judy Cho 博士， 转化遗传学教授兼院长，个性化医学研究所所长，（3）博士。 Jeremiah Faith，遗传学和基因组科学系副教授兼教务主任 微生物组转化中心。 环境：ISMMS 拥有优秀研究的悠久传统，是排名前 20 的医学院之一 西奈山胃肠病学部门一直被认为是美国国立卫生研究院 (NIH) 资助的前 10 名之一。 《美国新闻与世界报道》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 这种保持节制的手术涉及切除结肠和直肠， 从回肠建造一个小袋，作为粪便的盆腔内部储存器，并恢复肠道功能 大约 20% 的患者在最终手术阶段后两年内出现 CDLPI，最多可达 20%。 其中 50% 的患者对标准 IBD 疗法没有反应，需要手术摘袋和 迄今为止，在结肠切除术之前还没有办法预测哪些患者患有 UC。 将发展 CDLPI 和储袋失败 我们建议表征遗传变异、回肠转录组、 接受 IPAA RPC 的 UC 患者的微生物和代谢组学特征与 CDLPI 相关。 证实患有 CDLPI 的患者具有独特的高危遗传和回肠转录组特征 CDLPI 存在于造袋前结肠切除术时，并且随着时间的推移，暴露于 特定的微生物群。