This proposal explores expression of the rapidly inducible c-fos and heat shock genes following neural injury. Molecular mechanisms of injury are poorly understood and new indicators of injury are needed since many animal studies use histological stains to assess the efficacy of therapeutic drug regimens for ameliorating the CNS damage caused by stroke, excitotoxins, and head injury. Many histological stains have serious limitations including problems detecting early injury, particularly to single cells. Fos, the gene product of c-fos, is rapidly induced in the nuclei of single cells throughout cortex and amygdala following focal cortical lesions and focal cortical injections of NGF. Experiments will test the hypothesis that local release of NGF and other molecules at the sites of injury activate cholinergic neurons in the nucleus Basalis of Meynert (NBM) which in turn project upon and induce Fos in cells throughout cortex. We will determine (a) which cells express Fos and (b) which trophic substances, when injected into cortex or into NBM, induce Fos, detected immunocytochemically, and c-fos mRNA, detected using Northern blots and in situ hybridization. Heat shock proteins (HSPs) are also rapidly expressed following injury. Stroke, diffuse forebrain ischemia, systemic and local injections of kainic acid, and local injections of kynurenic acid and MK801 rapidly induce the heart shock protein, HSP72, in single neurons and glia. The time course and topographic distribution of HSP72 induction following ischemic injury will be described. This will be correlated with the regions where cell death or cell survival occurs on standard histological stains. The induction of HSP72 produced by excitatory amino acid agonists and antagonists will be studied in primary cultures of neurons and glia. Moreover, experiments will test whether induction of HSP72 proteins protects cultured neurons and glia from otherwise lethal injuries. Future studies will determine whether prior induction of either the heat shock or c-fos genes protects the brain from injury.
Showing the most recent 10 out of 107 publications
