Symptomatic and Functional Biomarkers of IVD Degeneration in a Small Animal Model

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DESCRIPTION (provided by applicant): Intervertebral disc (IVD) degeneration is a complex musculoskeletal pathology characterized by early onset of anatomical changes in the spine that may be associated with decreased patient mobility and increased symptomatic pain. In animal models, pain sensitivity, gait, and motor coordination have been shown to be reflective of degenerative musculoskeletal and inflammatory pathologies, such as arthritis. These measures have the potential to serve as minimally invasive biomarkers that translate to human pathology, but have not been well studied in models of IVD degeneration. Strong genetic links have been identified between IVD degeneration and single nucleotide mutations in genes encoding type IX collagen. Recently, mice with an inactivation of the Col9a1 gene (type IX collagen knockout) have been shown to spontaneously and prematurely develop IVD degeneration, including changes in proteoglycan content, cell death, and joint morphology that resemble human disease. This proposal will test for a relationship between functional, symptomatic, and anatomic markers of IVD degeneration in type IX collagen knockout mice to test the hypothesis that IVD degenerative changes can be detected through minimally invasive, non-sacrificial biomarkers of pain sensitivity, gait, and motor coordination. A longitudinal test design will be employed to detect premature onset of degenerative changes in knockout mice and associated symptomatic or functional changes at 6, 12, 24, and 48 weeks. Pain sensitivity will be evaluated using von Frey filaments (mechanical allodynia) and thermal plantar and tail flick tests (thermal hyperalgesia). Gait will be recorded using high speed digital video, and analyzed to quantify velocity, limb support phases, symmetry, step width, and stride length. Additionally, motor coordination will be assessed using rotarod treadmill, wire-hang, pole walking, and grip strength tests. These symptomatic and functional data will then be correlated to measures of IVD degenerative changes as assessed by MRI and histology. As minimally invasive, non-sacrificial biomarkers of IVD degeneration, these parameters may be used to rapidly screen the effects of disease interventions, track temporal changes in symptomatic pain and functional losses associated with IVD pathology, assess behavioral selection and functional limits directed by IVD degeneration, and provide a pain and functional characterization of a novel small animal model. The applicant will learn new methodologies in imaging, gait analysis, and symptomatic pain assessments, that will advance both the applicant's career and the translation of these biomarkers for the study of human disease. Thus, the objective of this proposal is to assess the efficacy of these biomarkers in a novel model of IVD degeneration.