Neurotoxicity is a serious dose-limiting complication in the chemotherapeutic treatment of cancer. Existing laboratory models are limited in their ability to determine the mechanism of toxicity, thus hindering efforts to reduce or reverse these often serious complications of treatment. The development of an in vitro model system using cultured dorsal root ganglia (DRG) would allow examination of the effect of neurotoxins, including cancer chemotherapeutic agents, on neurons. Axon cytoskeletal changes are an established mechanism of action of several neurotoxins and it is likely that many neurotoxic drugs also cause primary disruption or secondary alteration of the axon cytoskeleton. The cytoskeleton of cultured DRG neurites has not been fully characterized during normal development or in response to injury. For these studies, molecular biologic, ELISA and histologic techniques will be used to characterize this culture system. The following Specific Aims are proposed: 1. Characterize the neuronal cytoskeleton and cytoskeletal gene expression in cultured dorsal root ganglia and develop methods to promote a maturational changes in vitro. 2. Evaluate the effect of myelination and Schwann cell ensheathment on the neurite cytoskeleton and cytoskeletal gene expression in cultured DRG. 3. Analyze changes in the cytoskeleton of DRG cultures in response to axotomy and compare these changes to the in vivo axotomy model. 4. Investigate models of neurotoxic neuronal injury. This model system will allow the study of the mechanisms of neurotoxicity of varied agents by enabling detailed analysis of toxin induced changes at the molecular and cytoskeletal level. This will facilitate the long term goals of permitting rational development of pharmacological approaches to preventing or reversing neurotoxicity.
| Linskey, M E; Gilbert, M R (1995) Glial differentiation: a review with implications for new directions in neuro-oncology. Neurosurgery 36:1-21;discussion 21-2 |
