The investigator has identified a role for testosterone propionate (TP) in enhancing neuronal regeneration of the crushed facial nerve in adult hamsters. It is thought that testosterone mediates its actions through androgen receptors (AR) that are more prevalent in males than in females and are present at the surface of this particular neuronal subtype. Previously, a working model of the mechanism by which steroids augment peripheral nerve regeneration has been developed. The main objective of this project is to test specific aspects of this model, with particular focus on the initial injury phases of the regenerative response and on the role of the androgen receptor in these early phenomena.
The aims are to test the following 4 hypotheses. First, it was shown that TP administration coincident with facial nerve injury alters early stress responses of injured FMN. Two series of experiments, utilizing northern blot and immunoblot procedures in conjunction with heat shock protein 70 cDNA probes and antibodies will be used to determine the effect of TP on the stress response of injured FMN. Second, the effects of TP on facial nerve regeneration occur during the initial stages of the FMN injury response although all previous studies have used TP administration for lengthy time periods. To learn if TP can work early on, TP exposure will be limited to time periods of 6-2 hours after facial nerve injury and 2 series of analyses will be done. Radioisotopic labeling procedures will be used to determine the effects of limited Tp exposure on the rate of facial nerve regeneration, and in situ hybridization studies with cytoskeletal probes will be done to determine the effects of limited TP exposure on cytoskeletal response patterns throughout the recovery period. Third, the gender differences in the augmentation of facial nerve regeneration by TP are AR mediated. In 3 series of experiments, females will receive TP prior to facial nerve injury, in order to up-regulate levels of AR mRNA to those of males, and the effects of TP on facial nerve regeneration, and rRNA/cytoskeletal gene expression will be determined. Fourth, estradiol (E) acts via AR to augment racial nerve regeneration. It has been shown that E given from the time of facial nerve injury, results in an androgen- like acceleration of regeneration rates. Two series of experiments will be done. The effects of high doses of E in the presence of the anti-androgen, flutamide, and high versus low doses of E on the rate of regeneration will be determined. AR binding assays will also be done to determine if E binds to AR in the facial nucleus.
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