Paneth cell dysfunction and gut dysbiosis in experimental intestinal inflammation

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.