Role of gut microbiome dysbiosis and sustained inflammation in osteoarthritis - PROJECT SUMMARY Title: Role of gut microbiome dysbiosis and sustained inflammation in osteoarthritis This application seeks support for a specialty board certified veterinary surgeon embarking on an independent career as a translational clinical scientist. The applicant proposes a multi-disciplinary approach to study the role of the gut microbiome and immunome in osteoarthritis (OA) progression, with mentorship from leading experts in skeletal homeostasis and disease, osteoarthritis, microbiology, immunology, and pathology at the University of Colorado Anschutz Medical Campus (UCAnschutz) and Colorado State University (CSU). The applicant would work under the mentorship of: Michael Zuscik, PhD, in the Department of Orthopedics at University of Colorado Anschutz Medical Campus and Kelly Santangelo, DVM, PhD, and Steven Dow, DVM, PhD, in the Departments of Microbiology, Immunology, Pathology and Clinical Sciences at Colorado State University. The applicant’s proposal would leverage her research background in osteoarthritis and previous experience as a veterinary surgeon with clinical access to equine orthopedic patients to address the overall hypothesis that the gastrointestinal tract and joint microbiome in OA have expanded populations of specific pro-inflammatory bacterial populations that sustain local synovial inflammation in progressive OA using the relevant large animal (equine) model to address questions that would not be possible in human patients. Specifically, this proposal aims to 1) identify shared populations of pro-inflammatory bacteria in the gut and joints of horses with naturally occurring OA and systemic inflammation, 2) interrogate the impact of pro- inflammatory bacteria and their secreted products on activation of relevant joint immune cells, and 3) determine whether pathogenic bacteria are preferentially recognized by antibodies in synovial fluid and blood from horses with OA. The career development plan and training program described will specifically allow the applicant to develop depth of knowledge 1) in the role of the microbiome and bacterial metabolites in orthopedic pathology acquiring advanced expertise in next generation sequencing techniques, 2) develop skills in immunological methods including fluorescence activated cell sorting, immunocytochemistry, and immunoassay readouts, and 3) refine musculoskeletal pathology techniques. The candidate is a tenure-track early-career assistant professor with support from the Department of Clinical Sciences to remain in at least a 75% research commitment with 25% service/teaching commitment for the duration of the grant term if awarded. Further, she has her own dedicated laboratory space in the Translational Medicine Institute in the College of Veterinary and Biomedical Sciences at CSU and is supported by a transdisciplinary team of investigators with experience in microbiology, immunology and pathology. These studies aim to fill a critical gap in our understanding of how the dysbiotic gut microbiome and inflammasome drive progressive OA.
