The long term goals of our research are to understand the mechanism governing growth and degenerative processes in the adult central nervous system. Our previous work has provided the basis for a general hypothesis concerning some of the biochemical events that play key roles in determining the nature and extent of both growth and degenerative responses under a variety of pathological conditions. In particular we propose that the initial event leading to neuronal pathology triggers both degenerative processes (impairment of calcium regulation, activation of calcium-dependent protease, degradation of cytoskeletal proteins, increased formation of oxygen radicals) and regenerative growth processes (induction of ornithine decarboxylase (ODC), increased polyamine levels). The proposed experiments take advantage of our knowledge of the biochemical and morphological modifications that follow various types of alterations in hippocampal circuitry and function. Our previous studies have identified two categories of biochemical processes that can be used to quantify growth (ODC activity, polyamine levels) and degenerative responses (calpain activation, spectrin breakdown products).
The aims of the present proposal are to determine the generality of these mechanisms, to further specify the underlying biochemical processes and to evaluate the effects of treatments stimulating growth responses on the extent of degenerative responses. Specifically we propose to 1) compare the changes in the markers for growth and degeneration in different models of neuronal pathology in neonate and adult animals, 2) study the mechanisms underlying ODC induction in adult and neonate animals in vitro and in vivo, 3) determine the effects of ODC and polyamines on growth and degenerative responses in different models of neuronal pathology, 4) test the possible role of calcium- dependent proteases in the formation of oxygen radicals in various forms of neuronal pathology in adult and neonate animals, and 5) study the electrophysiological effects of polyamines and of agents promoting ODC induction in the vitro hippocampal slice preparation. These studies should provide a better understanding of the mechanisms regulating the balance between growth and degeneration and possibly provide tools to manipulate degenerative processes which might ultimately be applicable in a wide range of pathological conditions.
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