Our laboratory studies astrocytes, the most abundant cell type in the human brain. Some of the functions attributed to these cells include regulating the development and maintenance of neurons and oligodendrocytes, establishment of the blood-brain barrier, metabolism of neurotransmitters, potassium homeostasis, and contributing to memory formation. Our specific subject is the transcriptional regulation and biological functions of GFAP, an intermediate filament protein that is almost exclusively expressed in these cells. GFAP was selected for study because of this cell specificity, and also because its synthesis is turned on about the same time as astrocytes mature, and its activity increases dramatically following almost any CNS injury. Thus, study of GFAP transcription should yield insights into mechanisms governing development, reaction to injury, and cell specificity. The interesting regulation of the GFAP gene, and the fact that astrocytes have elaborated their own specific intermediate filament protein, predict an important role for GFAP in these cells. We have discovered two such roles. We have found that the absence of GFAP renders mice hypersensitive to traumatic spinal cord injury, revealing a novel role for GFAP in structural support. We have also discovered that mutations within the coding sequence of the GFAP gene are responsible for many cases of Alexander disease, a rare but often fatal neurodegenerative disorder of humans. In past work we have shown that a 2 kb 5'-flanking segment of the GFAP gene is capable of producing astrocyte specific expression of a linked reporter gene in transgenic mice. This promoter has been widely used by other laboratories to study CNS function and to develop disease models. We are presently trying to identify the factors responsible for the restriction of expression to astrocytes and that mediate the increased synthesis of GFAP following injury. For both of these properties we have narrowed our search to DNA segments as small as 50 bp, and are now working to identify the precise sequences required. We will then use this information to isolate and characterize the mediating transcription factors to parse out the signaling pathways involved. We are also working to increase the utility of the GFAP expression system by developing cassettes that are more dependably astrocyte-specific, direct expression to particular sub-regions of the brain, are more compact and have higher expression levels. In continuing studies of Alexander disease we are investigating the mechanism by which GFAP coding mutations produce the disorder. Mutation-specific antibodies are being developed to permit comparison of the properties of the mutant and wild type proteins in both mouse models and human patients. Proteomics/mass spec is being used to identify the proteins
Michael Brenner received his Ph.D. in Biochemistry from the University of California, Berkeley in 1970. He served on the faculty of Harvard College and Temple University Medical School, and was a Research Scientist at the National Institutes of Health before joining UAB in 1998. He is presently Professor of Neurobiology with a secondary appointment in the Department of Physical Medicine Rehabilitation.