Astrocytes are the major cell type of the central nervous system, wherein they perform a variety of critical roles.- Activities now attributed to these cells include participation in the development and maintenance of neurons and oligodendrocytes, formation of the blood-brain barrier, recycling of glutamate, and potassium homeostasis. Genetic defects in astrocytes have recently been found to cause Alexander disease, a fatal leukodystrophy;and astrocyte dysfunction has also been associated with several other neurological disorders, such as Alzheimer's disease, Down's syndrome and amyotrophic lateral sclerosis (Lou Gehrig's disease). In addition, in response to almost any kind of injury to the brain, astrocytes undergo a change called reactive gliosis, in which they greatly increase the synthesis and release of a large number of molecules. While some of these molecules are thought to ameliorate the injury, others are believed to inhibit repair, including blocking the regeneration of axons. Many fatal brain tumors are also thought to arise from astrocytes. Thus understanding and manipulating the role of astrocytes in the normal and diseased brain is likely of major clinical importance. We are approaching this goal by studying the transcriptional regulation of the gene encoding glial fibrillary acidic protein (GFAP), an astrocyte-specific protein whose synthesis is greatly increased during the reactive response. These studies will primarily be performed by analyzing expression patterns of reporter gene constructs in transgenic mice.
In Specific Aim 1 we will perform a detailed analysis of DMA segments that we have previously shown are likely to be important for GFAP gene activity. The objective is to identify the precise DMAsequences required, and then to use this information to isolate and characterize the mediating transcription factors to parse out the signaling pathways involved.
In Specific Aim 2 we will develop better tools for expressing transgenes in astrocytes. These tools include GFAP-based promoters that are more specific in their astrocyte specificity, and that are more potent. Relevance to Public Health: The information and tools developed under this proposal will facilitate investigation of the roles of astrocytes in development and disease, and will be used in gene therapy of CNS disorders.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Neurodegeneration and Biology of Glia Study Section (NDBG)
Program Officer
Fountain, Jane W
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Alabama Birmingham
Schools of Medicine
United States
Zip Code
Brenner, Michael (2014) Role of GFAP in CNS injuries. Neurosci Lett 565:7-13
Yeo, Sujeong; Bandyopadhyay, Susanta; Messing, Albee et al. (2013) Transgenic analysis of GFAP promoter elements. Glia 61:1488-99
Lee, Youngjin; Messing, Albee; Su, Mu et al. (2008) GFAP promoter elements required for region-specific and astrocyte-specific expression. Glia 56:481-93
Liu, Beihui; Wang, Shu; Brenner, Michael et al. (2008) Enhancement of cell-specific transgene expression from a Tet-Off regulatory system using a transcriptional amplification strategy in the rat brain. J Gene Med 10:583-92
Lee, Youngjin; Su, Mu; Messing, Albee et al. (2006) Astrocyte heterogeneity revealed by expression of a GFAP-LacZ transgene. Glia 53:677-87
de Leeuw, Bertie; Su, Mu; ter Horst, Maarten et al. (2006) Increased glia-specific transgene expression with glial fibrillary acidic protein promoters containing multiple enhancer elements. J Neurosci Res 83:744-53
Li, Rong; Johnson, Anne B; Salomons, Gajja et al. (2005) Glial fibrillary acidic protein mutations in infantile, juvenile, and adult forms of Alexander disease. Ann Neurol 57:310-26
Thyagarajan, Dominic; Chataway, Timothy; Li, Rong et al. (2004) Dominantly-inherited adult-onset leukodystrophy with palatal tremor caused by a mutation in the glial fibrillary acidic protein gene. Mov Disord 19:1244-8
Su, Mu; Hu, Huimin; Lee, Youngjin et al. (2004) Expression specificity of GFAP transgenes. Neurochem Res 29:2075-93
Lupien, Caroline; Brenner, Michael; Guerin, Sylvain L et al. (2004) Expression of glial fibrillary acidic protein in primary cultures of human Muller cells. Exp Eye Res 79:423-9