The survival and proper functioning of sympathetic neurons is dependent on nerve growth factor (NGF). This trophic dependencies age-related such that the cells become less dependent on NGF as they mature. When immature sympathetic neurons are deprived of NGF, they undergo an active dying process which requires new mRNA and protein synthesis, usually termed programmed cell death. There is evidence indicating that this phenomenon also exists in neurones dependent on other trophic factors. Recently, it was reported that the sympathetic neuronal cell death associated with NGF deprivation could be prevented by several agents, including cAMP analog and agents that increase intracellular cAMP level. Further evidence indicates that cAMP and NFG save neurons through different pathways. Considering the fact that sympathetic neurons become less NGF dependent as they mature, and cAMP, or some related events, mediates, the developmental decrease in NGF dependence. This proposal is designed to test the following hypotheses: 1. Intracellular cAMP level is a determinant of NGF dependence in sympathetic neurons during the normal maturation process. 2 Agents capable of saving NGF-deprived neurons do so by raising intracellular cAMP level; or alternatively, cAMP will potentiate the effects of agents that save NGF-deprived neurons. 3. In addition to NGF-dependent neurons, cAMP can rescue neurons dependent on other trophic factors. 4. An increase in cAMP level (or initiation of cAMP-dependent events) by herpes virus vector will alter trophic factor-deprivation induced neuronal cell death. There are several important aspect of the proposed research. First, the relationship between NGF and cAMP on neuronal survival can be clarified. Second, we will determine whether cAMP is able to prevent cell death of other neuronal cell types. If the result is positive, then cAMP may occupy a central role in keeping g neurons alive. Third, herpes virus vector will be used to prevent trophic factor deprivation-induced cell death. The development and perfection of the herpes virus vector in this project will be beneficial for future animal studies using this vector system. From this study we will gain important knowledge about neuronal cell death in general, a specific mechanism to intervene in the death process in particular, and one potential tool in alter the neuronal cell death under in vitro and perhaps in vivo conditions. It is anticipated that from this study we will be a step closer to understanding the complicate process of cell death in neurodegenerative diseases, and to design a possible remedy for these disease.
