Intestinal Intelectin-1 regulation of obesity development

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PROJECT SUMMARY/ABSTRACT This proposal describes a 4-year career mentored research project with the goal of defining the effects of intestinal Intelectin-1 (ITLN1) in microbial function and composition and its role in the genesis of obesity and early life weight gain. Successful completion of the research and training plan will enable the investigator to gain the skills necessary to secure independent funding and become an independent physician-scientist. The inves- tigator's long-term goal is to define how the host-microbiota interface modulates the risk of obesity early in life through multidisciplinary approaches and enable the design of preventative obesity strategies starting in the neonatal period. The research aims and career development plan will work towards mastery and independence in gnotobiology, gut anaerobic microbiology, and preclinical models of metabolism and proficiency in functional and bioinformatic analysis of the microbiota and translational research in early life. The primary co-mentors are Dr. Richard S. Blumberg – an expert in mucosal immunology and preclinical models to study gut-microbiota interactions – and Dr. Alessio Fasano – a leader in pediatric translational studies in the host-microbiome interface –at Mass General Brigham/Harvard Medical School. The collaborative and mentorship team comprises a local, multi-institutional group of experts in bioinformatics, intestinal microbial ecology, mucosal immunology, metabo- lism, and childhood obesity. The research proposal seeks to explore interactions between intestinal ITLN1 and microbes in the genesis of obesity. ITLN1 has been associated with obesity in humans, but the mechanism(s) behind(s) this association are unknown. The preliminary findings suggest that ITLN1 binds a particular subset of bacteria in vivo and modulates the metabolic activity of the microbiome. Furthermore, intestinal ITLN1 might protect against obesity in a microbiota-dependent manner. The overall hypothesis of this mentored research is that intestinal ITLN1 protects from obesity by modulating the metabolic activity of ITLN1-bound bacteria. In this proposal, we will use in vitro transcriptomic and phenotypic analysis of ITLN1-bound bacteria and bottom-up and bottom down microbiological approaches in conventional and gnotobiotic mice with and without ITLN1 to under- stand the effects of ITLN1 on intestinal microbes and seek to provide critical information about mechanisms by which ITLN1 in the intestine can influence the host-susceptibility to obesity. Furthermore, the applicant will ex- plore the translational implication of ITLN1 binding to microbes in infants with adequate and excessive weight gain during the first two years of life, as rapid weight gain in this critical window is associated with childhood obesity. Expected outcomes include direct evidence that loss of a single protein (ITLN1) in the intestinal epithe- lium leads to obesity and metabolic syndrome through its effects on the microbiota and the development of the investigator's expertise in the mechanistic study of the host-microbiota interface in obesity and translational stud- ies in early life. This career development award will set the stage for an independent research career focused on developing strategies to prevent and treat obesity targeting the host-microbiota interface in early life.