We propose to investigate the functions of mature astrocytes, a major class of glial cells in the mammalian central nervous system. We presently know a great deal about the properties of immature astrocytes, which can be easily isolated from neonatal rodent brains and cultured. Study of more mature astrocytes has been hindered by the inability to purify them and because these more mature astrocytes rapidly die in culture. Recently we have developed a method to isolate mature, protoplasmic astrocytes from postnatal mouse cerebral cortex. We have found that unlike the immature astrocytes, the mature astrocytes rapidly undergo apoptosis unless they are cultured together with endothelial cells. Using this new culture preparation, we propose to begin to investigate the functions of mature astrocytes. First, we will investigate the signaling mechanisms by which endothelial cells promote protoplasmic astrocyte survival. Second, we will investigate the functions of mature astrocytes purified from healthy mouse brains, by asking whether they promote neuronal survival, synaptogenesis, or myelination. Third, we will ask whether mature astrocytes by themselves can induce and maintain the blood-brain barrier and, if not, whether other neural cell types such as pericytes or neurons collaborate with astrocytes. Finally, we will investigate the relationship between healthy and reactive astrocytes. We will purify reactive astrocytes and compare their functions as well as their gene expression patterns by microarray profiling. We will then investigate the mechanisms by which normal astrocytes are induced to become reactive and whether the reactive astrocyte phenotype is stabile or can be induced to revert to a normal phenotype. These studies have potential to shed new light on the mysterious role of astrocytes in health and disease. For instance, understanding the blood-brain barrier may help us to develop new ways to deliver drugs into the brain. Understanding reactive gliosis may also lead to new treatments, as it contributes to the pathophysiology of neurodegenerative diseases, stroke, epilepsy, and limits regenerative CNS repair. ? ?
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