Paneth cell dysfunction and gut dysbiosis in experimental intestinal inflammation

描述（由申请人提供）：候选人是一名儿科胃肠病学家，在基础科学研究方法方面具有很强的背景，并致力于将这些技能应用于炎症性肠病（IBD）的研究。当前K 08提案的目标是获得实现候选人成为独立资助的医生-科学家的长期职业目标所需的高级机械培训，领导一个专注于开发新型，毒性最小的IBD疗法的实验室。具体来说，候选人的短期目标是：1）获得专业知识， 宿主-微生物相互作用的研究，包括询问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，包括研究复杂肠道微生物群落所需的技术; 3）通过生成支持未来NIH拨款申请的临界质量数据和出版物，建立独立研究领域。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。目前的建议的目的是了解一个特定的肠上皮亚型，潘氏细胞，在实验性肠道炎症的发展中的作用。该候选人假设，受损的潘氏细胞抗微生物活性与肠道微生物群的促炎性变化相关，这些变化易导致肠道炎症的发展。这一假设将使用一种新型的肠道炎症小鼠模型进行测试，该模型缺乏基因免疫相关的GT3家族M成员1（Irgm 1）。在目标1中，将使用标准技术以及专注于阐明潘氏细胞功能障碍机制的创新性离体测定来表征潘氏细胞杀微生物功能的改变。在目标2中，Irgm 1-/-肠道微生物群的促炎性改变将通过全局分析技术和新的功能测定来表征。这些目标通过提供上皮生物学机制方面的培训以及复杂微生物群落的研究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）指导和咨询团队，其中包括国际公认的，独立资助的研究人员，他们在宿主-微生物相互作用，潘氏细胞生物学和微生物生态学方面具有专业知识;和3）旨在促进独立性和国家认可的学术活动。最后，候选人的研究环境是基于一个杰出的学术研究机构（北卡罗来纳州在查佩尔山的大学），可以访问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），这些中心都是为支持拟议的研究而量身定制的。这种环境将提供一个富有成效的合作氛围，以实现所述的研究和培训目标。

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.