From studies of gonadal steroid hormone action on the brain, it is generally established that these agents exert neurotrophic effects on many aspects of neuronal viability and functioning. Recent clinical and experimental evidence suggests that gonadal may have a therapeutic role in promoting neuronal regeneration. We have recently demonstrated that systematic administration of the androgen, testosterone propionate(TP), to adult male hamsters accelerates functional recovery from facial paralysis induced by facial nerve crush. Importantly, facial motoneurons contain androgen receptors. How TP accomplishes this therapeutic effect is not known. The long term objective of our research is to determine the mechanism underlying the TP-acceleration of recovery from facial nerve damage. Toward that objective, the specific aims of this proposal will be to test the following 4 hypotheses. The first hypothesis to be tested is that TP accelerates recovery from facial paralysis following facial nerve crush by increasing the growth rate of regenerating axons and/or shortening the initial delay of sprout formation. Two series of experiments, involving radioisotopic labeling of axonally transported proteins, will be employed to assess the effects of TP on axonal regenerative properties. The second hypothesis to be tested is that the TP-induced acceleration of functional recovery following peripheral nerve injury is androgen receptor-mediated. Two series of experiments will be done to determine if the action of TP on injured neurons is androgen receptor-mediated. In the first, androgen receptors will be blocked, the facial nerve crush axotomized, and the effects of TP on functional recovery determined. In the second, a population of motor neurons that do not have androgen receptors (cranial nerve VI) will be subjected to crush axotomy and the effects of TP on functional recovery determined. The third hypothesis to be tested is that TP-accelerated recovery from facial paralysis following facial nerve crush involves alterations in ribosomal RNA gene expression in facial motoneurons. The effects of gonadal steroids in the brain are thought to occur through alterations in neuronal gene expression. Ribosomal RNA represents an abundant, readily quantifiable RNA species that is known to be affected by axotomy and by steroid hormone action on target neurons. In situ hybridization with a genomic ribosomal DNA probe will be employed to determine if significant alterations in the pattern of rRNA expression occur in injured facial neurons following TP exposure. The fourth hypothesis to be tested is that TP-accelerated recovery from facial paralysis following facial nerve crush involves alterations in protein synthesis within faci: motoneurons. Hormonal regulation of target tissue functioning is generally considered to occur through selective changes in the expression of proteins. Axotomy also has been demonstrated to selectively affect protein synthesis in regenerating neurons. Radioactive labeling and two-dimensional gel electrophoresis will be done to identify TP-induced changes in protein synthesis in injured facial neurons.
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