The astrocytic response to CNS injury has long been implicated in the failure of damaged axons to regenerate beyond the injured area. Recent experiments have demonstrated that reactive astrocytes, originally considered physical barriers to regenerating axons produce an extracellular matrix (ECM) that inhibits axon outgrowth. In vitro assays suggest that the inhibitory component of this ECM is associated with the expression of chondroitin sulfate proteoglycans (CS-PGs) and that decreasing CS-PG expression after injury would enhance axonal regeneration through areas of reactive astrogliosis. CS-PGs are a group of complex molecules whose synthesis in a variety of peripheral cells is upregulated by transforming growth factor-beta (TGF-beta). The role of TGF-beta on CS-PG expression in the CNS is less clear. TGF-beta and CS-PG levels are highest in embryonic animals and both are downregulated shortly after birth. TGF-beta levels increase following CNS injury and this increase is correlated temporally and spatially with the re-expression of CS-PGs. Preliminary data demonstrate that in response to TGF-beta, cultured astrocytes synthesize a neurite growth inhibitory CS-PG and that this response is blocked by the addition of TGF-beta neutralizing antibodies. Data demonstrating that CS-PG expression is blocked after CNS injury by the in vivo administration of these TGF-beta neutralizing antibodies is now included. Based on these significant findings, it is hypothesized that TGF-beta stimulates CS-PG production after CNS injury and that neutralizing TGF-beta bioactivity will enhance axonal regeneration in vivo. These hypotheses will be tested by: ( 1 ) determining whether TGF-beta regulates the production of CS-PG after CNS injury by continuous intraventricular delivery of TGF-beta neutralizing antibodies and assessing CS-PG levels in the injured area; (2) examining the expression of specific CNS CS-PGs in response to TGF-beta, and; (3) examining whether neutralizing the function of TGF-beta enhances axonal regeneration following spinal cord injury. These studies will help identify signals that stimulate the production of axon growth inhibitory CS-PGs by reactive astrocytes. Decreasing the expression of these inhibitory molecules, combined with the use of factors known to promote axon outgrowth, may lead to the development of comprehensive strategies designed to optimize axonal regeneration after CNS injury.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
First Independent Research Support & Transition (FIRST) Awards (R29)
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Neurology B Subcommittee 2 (NEUB)
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Michel, Mary E
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Emory University
Anatomy/Cell Biology
Schools of Medicine
United States
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Law, Alick K T; Gupta, Deepak; Levy, Shawn et al. (2004) TGF-beta1 induction of the adenine nucleotide translocator 1 in astrocytes occurs through Smads and Sp1 transcription factors. BMC Neurosci 5:1
Buck, Charles R; Jurynec, Michael J; Gupta, Deepak K et al. (2003) Increased adenine nucleotide translocator 1 in reactive astrocytes facilitates glutamate transport. Exp Neurol 181:149-58