Investigation of the dynamics and mechanisms of colitis-induced neuroinflammation - PROJECT ABSTRACT Inflammatory bowel diseases (IBDs), which entail debilitating gastrointestinal symptoms, affect millions of people worldwide. Interestingly, IBD patients suffer from anxiety & depression more often than the general population. Gastrointestinal symptoms of human IBDs are typically chronic and relapsing, but the co-occurring psychological abnormalities are relatively constant. Some studies have investigated the effect of active intestinal inflammation on the brain, but little work has been done to characterize changes to the brain during relapsing intestinal disease remission, when behavioral symptoms remain. Thus, the long-term goal is to understand colitis-induced neuroinflammatory dynamics and the mechanism through which they are conveyed. Neuroinflammation can be deleterious to the brain and contributes to the progression of many psychological & neurological diseases. The Round lab has identified two major neuroinflammatory phenotypes that may be contributing to the intestinal inflammation-induced psychological manifestations: (1) Calprotectin is elevated in the brain early and persistently during relapsing intestinal insult, and (2) monocyte and neutrophil infiltrate the brain ten days after colitis induction. Calprotectin can stimulate inflammation, leukocyte recruitment, and apoptosis in a variety of tissues and disease contexts; however, it is not well understood how calprotectin contributes to persistent colitis-induced neuroinflammation or what the functional role of the infiltrating immune cells is. Aim 1 will determine what cell type in the brain is responsible for the elevated calprotectin and its necessity for immune cell recruitment. Aim 2 will determine whether these cells are facilitating brain tissue repair or destruction. Finally, the mechanism of gut-brain communication during colitis still needs elucidation. It has been demonstrated that colitis can increase bone marrow granulopoiesis; thus, Aim 3 will test if changes in bone marrow during colitis are persistent and contribute to brain immune cell infiltration. Overall, this proposal will test the hypothesis that relapsing intestinal insult leads to elevated brain calprotectin levels that recruit multifunctional immune cells borne of persistently reprogrammed progenitor cells. In conclusion, this work will significantly enhance our understanding of the gut-brain axis during intestinal disease which can be leveraged for therapeutic benefit. This proposed research will facilitate the training of the applicant, Michaela Murphy, to prepare her for her career goal of becoming an independent scientific investigator in the gut-microbiota-brain axis field. It will develop her skills in 4 areas: (1) Knowledge & Experimental Design, (2) Technical Research Skills, (3) Science Communication, (4) Teaching & Mentorship, and (4) Leadership & Collaboration. Her sponsor, Dr. June Round, has the mentoring experience, supportive environment, and scientific expertise to ensure the successful execution of Michaela’s training plan, and the University of Utah provides ample resources to facilitate the efficient completion of this project and Michaela’s professional development.
