Role of gut microbiome dysbiosis and sustained inflammation in osteoarthritis

This application seeks support for a specialty board certified veterinary surgeon embarking on an independentcareer as a translational clinical scientist. The applicant proposes a multi-disciplinary approach to study therole of the gut microbiome and immunome in osteoarthritis (OA) progression with mentorship from leadingexperts in skeletal homeostasis and disease osteoarthritis microbiology immunology and pathology at theUniversity of Colorado Anschutz Medical Campus (UCAnschutz) and Colorado State University (CSU). Theapplicant would work under the mentorship of: Michael Zuscik PhD in the Department of Orthopedics atUniversity of Colorado Anschutz Medical Campus and Kelly Santangelo DVM PhD and Steven Dow DVMPhD in the Departments of Microbiology Immunology Pathology and Clinical Sciences at Colorado StateUniversity. The applicants proposal would leverage her research background in osteoarthritis and previousexperience as a veterinary surgeon with clinical access to equine orthopedic patients to address the overallhypothesis that the gastrointestinal tract and joint microbiome in OA have expanded populations of specificpro-inflammatory bacterial populations that sustain local synovial inflammation in progressive OA using therelevant 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 andjoints 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 bloodfrom horses with OA. The career development plan and training program described will specifically allow theapplicant to develop depth of knowledge 1) in the role of the microbiome and bacterial metabolites inorthopedic pathology acquiring advanced expertise in next generation sequencing techniques 2) develop skillsin immunological methods including fluorescence activated cell sorting immunocytochemistry andimmunoassay readouts and 3) refine musculoskeletal pathology techniques. The candidate is a tenure-trackearly-career assistant professor with support from the Department of Clinical Sciences to remain in at least a75% research commitment with 25% service/teaching commitment for the duration of the grant term ifawarded. Further she has her own dedicated laboratory space in the Translational Medicine Institute in theCollege of Veterinary and Biomedical Sciences at CSU and is supported by a transdisciplinary team ofinvestigators with experience in microbiology immunology and pathology. These studies aim to fill a criticalgap in our understanding of how the dysbiotic gut microbiome and inflammasome drive progressive OA.