Glycans in joint disease and glycosylated lubricin mimetics for osteoarthritis therapy

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Project Summary/Abstract This application seeks support for a specialty board certified (ACVS) equine veterinarian embarking upon an independent career as a translational clinical scientist. The applicant proposes a multi-disciplinary approach to study joint lubrication and osteoarthritis (OA), taking advantage of leading experts in cartilage lubrication mechanics, polymer chemistry and orthopedic research at Cornell University and synthetic glycobiology at Stanford University. The applicant would work in the laboratories of Dr. Lawrence Bonassar and David Putnam in the Department of Biomedical Engineering, in addition to her own dedicated laboratory space in the Veterinary Medical Center and animal research facilities at the College of Veterinary Medicine and Weill Medical College. Dr. Bonassar has published extensively on lubricin and cartilage biomechanics and also has an outstanding record of training graduate students and post-doctoral scientists. Dr. Putnam is an expert in polymer chemistry and the Founding Director of the Cornell Center for Biomaterials. Dr. Nixon is a DVM clinician scientist and large animal orthopedic surgeon, and Dr. Rodeo is an MD clinician scientist and orthopedic surgeon. Both Drs. Nixon and Rodeo are experts in orthopedic translational research with proven track records for training post-doctoral clinician scientists now in independent academic faculty positions. In addition to these primary mentors, the applicant has assembled a team of enthusiastic collaborators, including experts in advanced microscopy (Dr. Matthew Paszek) and synthetic glycobiology (Dr. Carolyn Bertozzi), who add both breadth and depth to the proposed research team. The research environment at Cornell is exceptionally strong in the relevant disciplines of biomedical engineering, translational orthopedic research, and chemical engineering, with the expertise of collaborator Dr. Bertozzi in synthetic glycobiology adding a significant dimension to the proposed research. The applicant's proposal would interrogate how the glycosylation of lubricin is altered in joint disease, the importance of glycosylation in the design and function of synthetic lubricin mimetics, and the ability of glycoengineered lubricin biomimetics to ameliorate disease in a rodent knee instability model of OA. Lectin blotting and mass spectrometry will be employed to characterize glycan profiles from both cell culture supernatants and normal and OA joints in Aim 1. In Aim 2, synthetic glycochemistry techniques will be utilized to synthesize, characterize and test the in vitro lubricating function of glycoengineered mimetics. Using glycoengineered lubricin mimetics synthesized from compounds provided by Drs. Putnam, Bonassar and Bertozzi, the applicant will investigate the ability of glycoengineered mimetics to prevent the progression of OA in the rat anterior cruciate ligament transection model of OA in Aim 3. It is expected that the candidate will begin this research as a junior faculty member in the Cornell University Department of Clinical Sciences with an 75% research commitment and 25% clinical service commitment.