Post-transcriptional Control of Gene Expression in Inflammatory Bowel Disease

炎症性肠病基因表达的转录后控制

基本信息

批准号：
9352839
负责人：
Louis Ghanem
金额：
$ 15.99万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-30 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9352839
关键词：
Acute Address Adverse effects Advisory Committees Alleles Animal Model Anti-Inflammatory Agents Anti-inflammatory Archives Autoimmune Diseases Binding Binding Proteins Binding Sites Biochemical Biogenesis Bioinformatics Biological Assay Child Care Childhood Chronic Chronic Disease Clinical Colitis Colon Cytokine Gene Cytokine Signaling Cytosine Data Data Analyses Defect Development Disease Effector Cell Enterocytes Environment Epithelial Epithelium Experimental Designs Faculty Family Fellowship Future Gastroenterologist Gastroenterology Gastrointestinal tract structure Gene Deletion Gene Expression Genes Genetic Genetic Transcription Genetic Translation Genetically Engineered Mouse Goals Grant Gut associated lymphoid tissue Human Immune response Inflammation Inflammation Mediators Inflammatory Inflammatory Bowel Diseases Inflammatory disease of the intestine Injury International Intestines Knock-out Laboratory Study Lead Link Maps Mediating Mentors Messenger RNA Modeling Molecular Mouse Strains Mucous Membrane Mus Nucleic Acid Regulatory Sequences Nucleotides Ontology Operon Outcome Pathogenesis Pathway interactions Pediatric Hospitals Pediatrics Pennsylvania Philadelphia Physicians Play Poly C Population Post-Transcriptional Regulation Predisposition Prevalence Process Proteins RNA RNA analysis RNA-Binding Proteins RNA-Protein Interaction Reagent Regulon Reporting Research Research Proposals Residencies Resolution Resources Role Scientist Severities Signal Pathway Site Stress Susceptibility Gene T-Lymphocyte Testing Tissues Training Training Programs Transcript Ulcerative Colitis Universities Writing adaptive immune response base career career development cis acting element cohort cytokine disabling disease experimental study gastrointestinal gastrointestinal function in vivo inflammatory milieu mRNA Stability mouse model novel diagnostics novel strategies novel therapeutic intervention programs protein expression protein function public health relevance skills transcriptome transcriptome sequencing

项目摘要

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.

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生涯，重点研究炎症性肠病 (IBD) 发病机制的分子机制申请人完成了住院医师培训。获得普通儿科博士学位，接受儿科胃肠病学临床进修培训，并加入费城儿童医院 (CHOP) IBD 中心，专注于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定义分子的独立医师科学家的职业生涯所需的。胃肠道慢性炎症的发展、功能和发病机制中基因表达的转录后控制的要求将是他的研究项目的核心目标。Stephen Liebhaber 博士是胃肠道转录后控制方面的国际思想领袖。真核基因表达将成为该提案的科学导师。此外，还将召集一批杰出的医学科学家在科学顾问委员会中任职，并支持候选人的职业发展。候选人将利用他们的专业知识和能力。在他朝着成为学术胃肠病学家和独立科学家的目标迈进时，CHOP 和宾夕法尼亚大学提供了出色且高度协作的培训环境和资源。本提案的研究目标是确定富裕家庭的角色。 RNA结合蛋白的胃肠道发育以及这些蛋白质对 IBD 严重性和进展的影响及其相关的转录后控制在炎症过程中发挥着关键作用。 PCBP 是一个重要的 RNA 家族。 -可充当炎症介质的结合蛋白在人类溃疡性结肠炎中显着改变；然而，申请人的初步研究已经证明了PCBP的强表达。小鼠结肠，证明 PCBP 对正常结肠发育至关重要，并表明 PCBP 影响结肠炎动物模型中的炎症严重程度。这些研究还揭示了可直接关联的结肠 mRNA 调节区域内 PCBP2 结合位点的显着聚集。该研究的目标是将由 PCBP（PCBP“调节子”）协调的转录后调节网络的识别与对特定相互作用重要的机制研究相结合。这些实验将代表首次转录组规模的分析，揭示蛋白质-RNA相互作用的动态变化以及这些相互作用在IBD模型中的功能后果。