| Budget Amount *help |
¥14,100,000 (Direct Cost: ¥14,100,000)
Fiscal Year 2005: ¥4,100,000 (Direct Cost: ¥4,100,000)
Fiscal Year 2004: ¥4,800,000 (Direct Cost: ¥4,800,000)
Fiscal Year 2003: ¥5,200,000 (Direct Cost: ¥5,200,000)
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| Research Abstract |
To explore the mechanism of axon guidance of the injured neurons in the cetral nervous system (CNS), we screened the genes whose expression was changed after stimulation with neurotrophins using microarray technique. We got more than one hundred genes that showed enhanced expression. We focus on several genes that are expected to play a role in axon guidance, and decide to perform detailed analysis. We found that chimaerins are involved in desensitization of the neurons to some inhibitory molecules. The expression of chimaerins are enhanced in the cerebellar granule neurons after exposure to neurotrophins. When chimaerins are ectopically overexpressed, inhibition of neurite outgrowth by myelin-associated glycoprotein is reduced to the control level. In contrast, the effect of prior exposure to neurotrophins is abolished by the gene knockdown of chimaerins using siRNA. Thus, chimaerins may promote axon regeneration after injury to the CNS. In addition, we are interested in another gene, repulsive guidance molecule (RGM). RGMa inhibits mammalian CNS neurite outgrowth by a mechanism dependent on the activation of the Rho/Rho-kinase pathway. RGMa expression is observed in oligodendrocytes, myelinated fibers, and neurons of the adult rat spinal cord, and is induced around the injury site following spinal cord injury. We developed an antibody to RGMa that efficiently blocks the effect of RGMa in vitro. Intrathecal administration of the antibody to rats with thoracic spinal cord hemisection results in significant axonal growth of the corticospinal tract, and improves functional recovery. Thus, RGMa plays an important role in limiting axonal regeneration after CNS injury, and the RGMa antibody offers a possible therapeutic agent in clinical conditions characterized by a failure of CNS regeneration.
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