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

这个项目将描述基因变异、回肠转录组、微生物和代谢组谱。 药物难治性溃疡性结肠炎(UC)患者需要行带回肠的修复性直肠切除术(RPC) 袋状肛门吻合术(IPAA)，随后发展为克罗恩病样膀胱炎(CDLPI)。 我们的目标是确定与CDLPI相关的风险经济学特征。 应聘者：此应用程序的主要目标是支持Maia Kayal博士发展成为 独立的、面向患者的炎症性肠病(IBD)领域的翻译研究员。Dr。 Kayal的职业目标是成为一名独立研究员，拥有分析集成方面的专业知识 回答IBD领域高影响力临床问题的方法论。为了实现这一目标，卡亚尔博士 制定了培训计划，重点是发展以下技能：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，4) 统计遗传学的临床应用。她已经组建了一支强大的多学科指导团队， 西奈山伊坎医学院(ISMMS)与(1)医学教授Marla Dubinsky博士和 儿科，儿科消化科主任，范斯坦IBD中心联席主任，(2)朱迪·赵医生， 翻译遗传学教授兼院长，个性化医学研究所所长，以及(3)Dr。 耶利米·费思，遗传学和基因组科学系副教授兼教研室主任 微生物组翻译中心的。 环境：ISMMS有着优秀的研究传统，是排名前20位的医学院之一 在国立卫生研究院的资助中。西奈山胃肠病学部一直被认为是前十名之一 《美国新闻》和《世界报道》在全国的研究和临床护理部门。 研究：高达30%的治疗难治性UC患者将需要手术，最常见的是 具有IPAA的RPC。这种保留大小便失禁的手术包括切除结肠和直肠， 回肠造袋作为盆腔内储便器的建立及肠道修复 连续性。大约20%的患者在最后手术阶段的两年内发展为CDLPI，并且高达 其中50%的患者对标准的IBD治疗无效，需要手术摘除眼袋和 永久性造口术。到目前为止，还没有办法在切除结肠之前预测哪位UC患者 会导致CDLPI和邮袋故障。我们建议描述基因变异，回肠转录组， 接受RPC和IPAA的UC患者中与CDLPI相关的微生物和代谢组学特征。我们 假设CDLPI患者具有独特的高危遗传和回肠转录特征 在结肠切除时出现，在造袋之前，CDLPI随着时间的推移而被暴露于 特定的微生物区系。

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.