The central nervous system reacts to injury by changes in the number and form of astrocytes (gliosis). The signals which initiate and control astrocytic proliferation and differentiation are unknown. Reactive gliosis differs between the developing and the mature brain, and the control signals may also differ. We postulate that growth factors, including EGF, FGF, PDGF, GMF, and GCSF, which are known to interact with neural tissue, are a major part of these control signals. We will study the regulation of gliosis by two methods. We will isolate the cell involved by purifying astrocytes in primary cell culture. Culture purity will be checked by use of cell specific antigens and enzyme activities. We will study the effect of growth factor treatments of astrocytes on proliferation and DNA synthesis, internal metabolism including glycogen storage, and cytoarchitecture including GFAP, microfilaments, and microtubules, as demonstrated by immunofluorescence. Cell surface changes will be studied through changes in motility, substrate adhesion, and responses to receptor-acting modulators. We will study the mechanism of action of the growth factors through binding studies, sequestration and processing of factors, protein kinase activation, membrane and nuclear protein phosphorylation, and activation of ornithine decarboxylase and RNA polymerase. We will study interaction between factors and modulation of their responses by glucocorticoid and thyroid hormones. Parallel studies will involve brain lesions, after which growth factor content and mechanisms will be evaluated. Two different lesion types will be used: traumatic (knife) and ischemic-hypoxic. Brain sections will be examined histologically and immunochemically for GFAP and growth factors. Astrocytes from lesioned brains will be studied in culture, and assayed for factor binding and membrane phosphorylation. Lesioned brain extracts will be tested for stimulation of 3H-thymidine incorporation and alteration of factor binding. We will attempt to modify the gliosis reaction in brain with factors and factor-toxin conjugates. The ontogeny of factor binding and content will be studied, including brain regions. We hypothesize that the minimal glial reaction of fetal brain to injury may be factor-related.
| Huff, K R; Schreier, W (1990) Fibroblast growth factor inhibits epidermal growth factor-induced responses in rat astrocytes. Glia 3:193-204 |
