Paneth cell dysfunction and gut dysbiosis in experimental intestinal inflammation

实验性肠道炎症中的潘氏细胞功能障碍和肠道生态失调

• 批准号: 8711435
• 负责人: Ajay S Gulati
• 金额: $ 15.42万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8711435
• 关键词: Absenteeism at work; Adverse effects; Affect; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Area; Attenuated; Bacteria; Basic Science; Biological Assay; Biology; Cell physiology; Cells; Cellular Morphology; Cellular biology; Childhood; Chronic; Clinical Sciences; Colitis; Communities; Comorbidity; Complement; Complex; Computational Biology; Crohn' s disease; Data; Development; Disease; Ecology; Elements; Environment; Epithelial; Equilibrium; Exhibits; Family; Fostering; Foundations; Functional disorder; Funding; Future; Gastroenterologist; Gastrointestinal tract structure; Genes; Germ-Free; Goals; Grant; Guanosine Triphosphate Phosphohydrolases; Health Care Costs; Healthcare; Homologous Gene; Hospitalization; Host resistance; Human; Immune response; Immune system; Immunity; Immunosuppression; Immunosuppressive Agents; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Inflammatory disease of the intestine; Institutes; Institution; Integration Host Factors; Interleukin-10; Intestinal Diseases; Intestines; Investigation; Laboratories; Lead; Learning; Ligands; Link; Measures; Mentorship; Muramidase; Mus; North Carolina; Operative Surgical Procedures; Organism; Paneth Cells; Pathogenesis; Patients; Physicians; Play; Positioning Attribute; Preventive; Proteins; Public Health; Publications; Quality of life; Relative (related person); Research; Research Methodology; Research Personnel; Research Training; Role; Schools; Scientist; Sequence Analysis; Sodium Dextran Sulfate; Statistical Models; Surface; Techniques; Testing; Therapeutic; Training; Transcript; Translational Research; United States; United States National Institutes of Health; Universities; Wild Type Mouse; antimicrobial; antimicrobial peptide; base; career; career development; commensal microbes; deep sequencing; design; disorder risk; gastrointestinal; gut microbiota; innovation; intestinal crypt; member; microbial; microbial community; microbicide; microorganism interaction; mouse model; new therapeutic target; novel; planetary Atmosphere; prevent; rRNA Genes; risk variant; skills; tool

DESCRIPTION (provided by applicant): The candidate is a pediatric gastroenterologist with a strong background in fundamental basic science research methods, and an established commitment to apply these skills to the study of inflammatory bowel diseases (IBD). The objective of the current K08 proposal is to obtain the advanced mechanistic training required to achieve the candidate's long-term career goal of becoming an independently funded physician- scientist, leading a laboratory focused on developing novel, minimally-toxic IBD therapies. Specifically, the candidate's short-term goals of this proposal are: 1) to acquire expertise in the study of host-microbial interactions, including the tools needed to ask mechanistic questions regarding these interactions; 2) to learn the fundamental principles of microbial ecology, including the techniques required to study complex gut microbial communities; and 3) to establish an area of independent research by generating a critical mass of data and publications that will support future NIH grant submissions. The candidate's overall research goal is to understand the mechanisms by which host epithelial dysfunction promotes bacterial imbalances in IBD patients. The objective of the current proposal is to understand the role of a specific intestinal epithelial subtype, the Paneth cell, in the development of experimental intestinal inflammation. The candidate hypothesizes that impaired Paneth cell antimicrobial activity is associated with pro-inflammatory changes of the gut microbiota that predispose to the development of intestinal inflammation. This hypothesis will be tested using a novel mouse model of intestinal inflammation deficient for the gene Immunity-related GTPase family M member 1 (Irgm1). In Aim 1, alterations of Paneth cell microbicidal function will be characterized using standard techniques, as well as innovative ex vivo assays focused on elucidating mechanisms of Paneth cell dysfunction. In Aim 2, pro-inflammatory alterations of the Irgm1-/- intestinal microbiota will be characterized through global profiling techniques and novel functional assays. These aims support the candidate's career development by providing training in mechanistic aspects of epithelial biology, as well as the study of complex microbial communities. Additional key elements of the candidate's training plan include: 1) advanced coursework in computational biology, sequence analysis, and statistical modeling; 2) a mentorship and advising team, which includes internationally-recognized, independently-funded investigators with expertise in host-microbial interactions, Paneth cell biology, and microbial ecology; and 3) scholarly activities designed to foster independence and national recognition. Finally, the candidate's research environment is based in a pre- eminent academic research institution (the University of North Carolina at Chapel Hill) with access to NIH- funded centers (including the Translational and Clinical Sciences Institute and Center for Gastrointestinal Biology and Disease) that are tailored to support the proposed studies. This environment will provide a productive and collaborative atmosphere in which to accomplish the described research and training goals.

描述（由申请人提供）：候选人是一名儿科胃肠病学家，具有强大的基础科学研究方法背景，并且已确定将这些技能应用于炎症性肠病研究（IBD）的既定承诺。当前K08提案的目的是获得实现候选人的长期职业目标所需的先进机械培训，即成为一名独立资助的医师 - 科学家，领导着一个专注于开发新颖的，微不足道的IBD疗法的实验室。具体而言，该提案的候选人的短期目标是：1）获得专业知识 研究宿主微生物相互作用，包括提出有关这些相互作用的机械问题所需的工具； 2）学习微生物生态学的基本原理，包括研究复杂的肠道微生物群落所需的技术； 3）通过产生大量数据和出版物来建立独立研究领域，以支持未来的NIH赠款提交。候选人的总体研究目标是了解宿主上皮功能障碍促进IBD患者细菌失衡的机制。当前建议的目的是了解特定的肠上皮亚型Paneth细胞在实验性肠炎发展中的作用。候选人假设受损的Paneth细胞抗菌活性与肠道菌群的促炎变化有关，这种变化易于肠道炎症的发展。该假设将使用缺乏基因免疫相关的GTPase家族M成员1（IRGM1）的新型肠炎症的小鼠模型进行检验。在AIM 1中，将使用标准技术以及针对阐明Paneth细胞功能障碍的机制的创新的离体分析来表征Paneth细胞微生物功能的改变。在AIM 2中，将通过全球分析技术和新型功能测定法对IRGM1 - / - 肠菌群的促炎性改变进行表征。这些目标通过在上皮生物学的机理方面以及对复杂微生物群落的研究方面提供培训来支持候选人的职业发展。候选人培训计划的其他关键要素包括：1）计算生物学，序列分析和统计建模的高级课程； 2）一个指导和咨询团队，其中包括具有国际认可的，独立资助的研究人员，具有宿主微生物相互作用，Paneth Cell Biology和微生物生态学方面具有专业知识； 3）旨在促进独立和国家认可的学术活动。最后，候选人的研究环境基于一家著名的学术研究机构（北卡罗来纳大学教堂山分校），该研究机构可访问NIH资助的中心（包括转化和临床科学研究所和胃肠道生物学和疾病中心），该中心量身定制，该研究所量身定制，这些中心量身定制，这些中心是为支持的研究而量身定制的。这种环境将为实现所描述的研究和培训目标提供富有成效的协作氛围。