Herniation of the intervertebral disc (IVD) may be associated with nerve root compression and biochemical irritation that contributes to inflammatory cell infiltration and associated generation of pain or radiculopathy. Tumor necrosis factor-a (TNFa) is a pro-inflammatory cytokine that is thought to be an early mediator of radiculopathy and neuropathic pain in herniated IVD. TNFa-induced inflammation is regulated by the transcription factor NF-kB, with data showing that NF-kB antagonism can reduce nociceptive pain following peripheral nerve injury. The main hypothesis of work proposed in this NRSA Fellowship is that regional NF-kB activity, determined via noninvasive, longitudinal in vivo imaging, has a direct relationship to rodent function and pain-related behaviors in a model of peripheral nerve injury. The secondary hypothesis is that localized inhibition of NF-kB in the region of nerve injury can modify pain-related behaviors.
In Aim 1, a model of chronic constriction injury (CCI) of the sciatic nerve will be developed in transgenic mice (NFkB-RE-Luc) containing a luciferase NF-kB reporter. Regional NF-kB activity in the nervous system will be monitored longitudinally and non-invasively via in vivo luminescence imaging, along with time-matched measures of function (e.g., gait), pain-related behaviors (mechanical and thermal hypersensitivity, running wheel activity), and characterization of the inflammatory cell infiltrate. Measures of function, pain, and inflammatory cell populations will be correlated with regional NF-kB in the CCI and sham-operated controls in order to evaluate the contributions of NF-kB to symptoms and dysfunction.
In Aim 2, the therapeutic efficacy of curcumin as an NF-kB inhibitor will be evaluated following CCI via noninvasive, in vivo imaging and markers of function and pain-related behaviors. Curcumin depots will be delivered perineural to the sciatic nerve following CCI in NFkB-RE-Luc transgenic mice, and mice will be tracked longitudinally for NF-kB activity via in vivo luminescence imaging. A separate set of animals will be similarly studied following CCI and perineural delivery of the specific NF-kB inhibitor, SC514. Measures of function, pain behaviors, and inflammatory cell characterizations will be obtained at all times and examined for correlations with NF-kB activity in both models, in order to assess an ability for local curcumin delivery to antagonize NF-kB activity, as well as symptoms and dysfunction associated with CCI. The applicant will work with the Sponsor and mentoring team to learn new techniques in state-of-the-art in vivo imaging, gait analysis, and pain assessments that will advance both the applicant's career and the translation of imaging and functional biomarkers for the study of musculoskeletal disease. The applicant will obtain broader training in research methodology, animal models, grant and manuscript preparation and responsible conduct in research that will prepare him for an academic career in bioengineering.
This project will investigate the contributions of a molecule regulating neuroinflammation, NF-kB, on function and pain following peripheral nerve injury. Noninvasive and longitudinal in vivo imaging will be used to monitor NF-kB activity in a model of peripheral neuropathy and to relate its activity to measures of gait and pain-related behaviors. A goal of this project is to develop in vivo imaging as a biomarker of neuropathy, with potential to impact the clinical treatment of radiculopathy in human subjects.
