We have shown that the rabbit disc degeneration model, which is induced by puncturing the annulusfibrosus with needles of defined gauges, resulted in reproducible, degenerative changes that could bequantitatively assessed. Our initial hypothesis that an injection of the growth factor, osteogenic protein-1, isable to regenerate the intervertebral disc was shown to be true using this model. This promising proteininjection therapy approach will soon be translated into a Phase I clinical trial as the first injection therapyusing a growth factor. The approaches in the proposed funding period are to: (1) test if the injection of agrowth factor into a disc also stimulates repair in a more clinically relevant model using adult rabbits; (2)expand therapeutic approaches to the application of cytokine inhibitory molecules; and (3) delineate thelimitations of such therapy under conditions where nutrition levels in the disc are compromised. In addition,efforts will be extended to identify changes in nerve-related cytokines, i.e. nerve growth factor, in the rabbitmodel and in cadaveric samples, as potential surrogate markers of low back pain. Hypothesis 1: Discdegeneration can be delayed or reversed by manipulating the balance between anabolic and catabolicpathways; some manipulations will result in decreased pain associated with disc degeneration.
In SpecificAim 1, we will test if growth factors (osteogenic protein-1, growth differentiation factor-5) and/or inhibitorymolecules of cytokines (interleukin-1 receptor antagonist, tumor necrosis factor-a soluble receptor) delay theprogression of disc degeneration or restore the degenerated disc using an in vivo protein injection in amature rabbit chronic disc degeneration model. Hypothesis 2: Compromised nutrient transport through theendplate limits cell-mediated disc repair induced by the application of a growth factor.
In Specific Aim 2 wewill investigate changes in nutrient transport in the rabbit annular puncture model of disc degeneration andidentify the presence of a critical level of nutrient transport that is deleterious to matrix metabolism. Low backpain is responsible for enormous human suffering, high health care costs and significant socioeconomiclosses. Although the etiology of back pain is often unknown, the intervertebral disc is a significant source ofback problems. The results from this study will advance the field of biological treatment for intervertebraldisc degeneration.
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