Post-transcriptional Control of Gene Expression in Inflammatory Bowel Disease

 描述（由申请人提供）：拟议的3年培训计划的目标是发展申请人作为学术胃肠病学家的独立研究职业生涯，专注于炎症性肠病（IBD）发病机制的分子机制。申请人完成了普通儿科的住院医师培训，儿科胃肠病学的临床奖学金培训，并加入了费城儿童医院（CHOP）IBD中心的教师，专注于IBD儿童的护理。候选人的近期目标是发展和完善实验设计，数据解释，资助写作和实验室管理的基本技能，这些技能是成功过渡到独立医生-科学家职业所必需的。定义基因表达的转录后控制在胃肠道慢性炎症的发展，功能和发病机制的分子要求将是他的研究计划的核心目标。Stephen Liebhaber博士是真核基因表达转录后控制领域的国际思想领袖，他将担任该提案的科学导师。此外，还召集了一批杰出的医学科学家，在科学咨询委员会任职，并支持候选人的职业发展。候选人将利用他们的专业知识以及CHOP和宾夕法尼亚大学提供的优秀和高度协作的培训环境和资源，因为他朝着成为学术胃肠病学家和独立科学家的目标前进。该提案的研究目标是确定丰富的RNA结合蛋白家族在胃肠道发育中的作用以及这些蛋白质对IBD严重程度和进展的影响。RNA结合蛋白及其相关的转录后控制在炎症过程中起着关键作用。多聚C结合蛋白（PCBP）是一个重要的RNA结合蛋白家族，可作为炎症介质。PCBP的基因表达在人类溃疡性结肠炎中显著改变;然而，这些变化的功能效应仍不清楚。申请人的初步研究已经记录了小鼠结肠中的稳健的PCBP表达，证明了PCBP对于正常结肠发育是必需的，并且显示了PCBP影响结肠炎动物模型中的炎症严重性。这些研究还揭示了在结肠mRNA的调控区域内PCBP 2结合位点的显著聚类，其可以直接与IBD相关途径相关联。研究目标将结合识别由PCBP协调的转录后调节网络（PCBP“调节子”）与对胃肠道功能和免疫反应重要的特定相互作用的机制研究。这些实验将代表第一个转录组规模的分析，揭示了蛋白质-RNA相互作用的动态变化以及IBD模型中这些相互作用的功能后果。

 DESCRIPTION (provided by applicant): The goal of the proposed 3-year training program is the development of the applicant's independent research career as an academic gastroenterologist focused on molecular mechanisms in the pathogenesis of Inflammatory Bowel Disease (IBD). The applicant completed residency training in General Pediatrics, clinical fellowship training in Pediatric Gastroenterology and has joined the faculty of the IBD Center at the Children's Hospital of Philadelphia (CHOP) focusing on the care of children afflicted with IBD. The candidate's near-term goals are to develop and refine the essential skills of experimental design, data interpretation, grant writing, and lab management that will be required for a successful transition to a career as an independent physician- scientist. Defining the molecular requirements for post-transcriptional control of gene expression in the development, function, and pathogenesis of chronic inflammation in the gastrointestinal tract will be the core aim of his research program. Dr. Stephen Liebhaber, an international thought leader in post-transcriptional controls of eukaryotic gene expression, will be the scientific mentor for this proposal. In addition, a group of eminent physician-scientists has been assembled to serve on a Scientific Advisory Committee and support the candidate with his career development. The candidate will draw upon their expertise and the outstanding and highly collaborative training environment and resources available at CHOP and the University of Pennsylvania as he advances toward his goal of becoming an academic gastroenterologist and independent scientist. The research goal of this proposal is to determine the role(s) of an abundant family of RNA-binding proteins in gastrointestinal development and the impact of these proteins on the severity and progression of IBD. RNA-binding proteins and their associated post-transcriptional controls play a critical role in inflammatory processes. The poly-C binding proteins, PCBPs, comprise an important family of RNA-binding proteins that can serve as mediators of inflammation. Gene expression of the PCBP's is significantly altered in human Ulcerative Colitis; however, the functional effect of these changes remains unclear. Preliminary studies by the applicant have documented robust PCBP expression in the mouse colon, demonstrated that PCBP's are essential for normal colonic development, and shown that PCBP's impact inflammation severity in an animal model of colitis. These studies also have revealed a remarkable clustering of PCBP2 binding sites within regulatory regions of colonic mRNAs that can be directly linked to IBD-related pathways. The research Aims will couple the identification of post-transcriptional regulatory networks coordinated by PCBP's (the PCBP `regulon') with mechanistic studies of specific interactions important for gastrointestinal function and immune responses. The experiments will represent the first transcriptome-scale analysis that uncovers dynamic changes in protein-RNA interactions and the functional consequences of these interactions in models of IBD.