Mining host-microbe interactions in the neonatal pancreas to combat diabetes

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Project Abstract After birth, newborns are exposed to a wide array of environmental microbes, which rapidly colonize the infant gastrointestinal tract and then gradually increase in diversity during the first years of the child’s life. Interestingly, reduced diversity of the resident microbiota can be used to predict Type 1 Diabetes (T1D) onset in genetically susceptible children, suggesting that early life microbiota diversity is critical in preventing diabetes. Concurrent with initial colonization and diversification of the microbiota, insulin-producing β-cells undergo essential postnatal developmental processes. My graduate work showed that zebrafish require intestinal bacteria for post-hatching proliferation of β-cells. In my postdoc I have gone on to show that germ-free mice also have significant deficits in β-cell mass and insulin production capacity which can be attributed to loss of microbial stimuli during a specific window of postnatal life corresponding with β-cell developmental milestones. I have also found that unique bacteria that are enriched during this time are sufficient to restore β-cell development in germ-free mice. Therefore, I hypothesize that specific microbes induce neonatal β-cell development and that the lack of microbial diversity that occurs prior to T1D limits the establishment of neonatal β-cells and reduces the chance to outpace autoimmune destruction. My background in host-microbe interactions and pancreatic development make me uniquely poised to address this question and the aims herein will provide me with essential training that will both advance this project as well as my own career goals. I propose to build upon my existing expertise in gnotobiology by seeking additional training in immunology and diabetes disease models to address important immune phenotypes involved in β-cell development and to test whether microbes with effects on β-cell development can modulate disease severity. This training will add new dimension to my knowledge base that will be broadly applicable to my goal of leading a lab at a top-tier research institution studying the role of the resident microbiota in pancreatic health and disease. I believe these avenues of research have the potential to alter our understanding and approach to pancreatic disease etiologies, and my long-term vision is to develop novel approaches in the fight against diabetes and pancreatic cancer that will improve the quality of human life. To ensure I succeed in my endeavor to establish a successful independent lab, I have assembled a team of supportive faculty mentors who are leading experts in the immunology and diabetes fields. The University of Utah is matchless for this proposal, as it has a concentration of exceptional researchers who collaborate through institutional organizations such as the Diabetes and Metabolism Research Center. Since graduate school I have successfully built collaborations and sought out the expertise that have carrier my ideas herein forward from their inception. This proposal is no exception, and I plan to develop it into a successful platform in my own lab that can be harnessed toward the prevention and treatment of diabetes.