1999 Fiscal Year Final Research Report Summary
The roles of cytokines and neurotrophins in the regenerative process of nervous system
| Project/Area Number |
09480215
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Nerve anatomy/Neuropathology
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| Research Institution | Wakayama Medical University |
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Principal Investigator |
SENBA Emiko Wakayama Medical Univ., School of Medicine, Prof., 医学部, 教授 (00135691)
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| Co-Investigator(Kenkyū-buntansha) |
NEMOTO Kiyomitsu Shizuoka Pref.Univ., School of Pharmac.Sci., Lecturer, 薬学部, 講師 (90189366)
UEYAMA Takashi Wakayama Medical Univ., School of Medicine, Lecturer, 医学部, 講師 (50264875)
MORIKAWA Yoshihiro Wakayama Medical Univ., School of Medicine, Lecturer, 医学部, 講師 (60230108)
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| Project Period (FY) |
1997 – 1999
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| Keywords | IL-6 family cytokines / neurotrophins / spinal cord injury / LIF / BDNF / AP-1 / dorsal root ganglion / adenovirus |
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| Research Abstract |
The involvement of cytokines and neurotrophic/neuroprotective factors in the process of injury/regeneration were investigated in various regions of the nervous system. Three types of injury models were prepared in rats ; (1)chronic constriction injury (CCI) or axotomy of the sciatic nerve, (2) crush injury of the spinal cord and (3) focal cerebral ischemia/reperfusion model. The spacial and temporal expression patterns of proteins and mRNAs of IEGs, cytokines and neurotrophins were investigated and cell types expressing thse molecules were determined. Expression of receptor components of IL-6 family cytokines, such as gp130, LIFRβ, IL-6R, OSMR, and signal transduction molecules of JAK-STAT pathway were investigated in the brain of rats and mice, in order to explore the roles of cytokines of this family in the nervous system. We found that these receptor components were expressed in cerebellar Purkinje cells. Overexpression of LIF in mice induced marked dendritic atrophy of Purkinje cel
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ls. Reorganization of dendro-dendritic synapses in the ex vivo model of superior cervical ganglion was inhibited by addition of serum in the medium, indicating that serum-derived factors are involved in the regulation of dendritic morphology of neurons. Experiments in the peripheral tissues, such as muscles, cornea and stomach, indicated that cytokines play important roles in the regeneration process, which is triggered by IEGs expression after injury. Migration of corneal epithelial cells was not initiated in c-fos knockout mice and in cultured cornea treated with antisense ODNs for c-fos and c-jun mRNAs. We showed that AP-1 is also involved in the regulation of BDNF and NT-3 gene expression using vascular smooth muscle cells. AP-1 was shown to negatively control the expression of NT-3 gene. E1A-and E1B-deleted adenovirus (AdV) containing EGFP reported gene insert under the control of CAG promoter was constructed and used in the in vivo experiment. Injection of this AdV-EGFP into the sciatic nerve or in the skin resulted in labeling of DRG neurons. Less
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[Publications] Kinoshita, Y., Ueyama, T., Senba, E., Terada, T., Nakai, K.and Itakura, T: "Differential expression of c-fos, heat shock protein 70, neurotrophins and cyclo-oxygenase-2 mRNA in response to focal cerebral ischemia/reperfusion in rats."J.Neurotranuma. (in press).
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[Publications] Morikawa, Y., Tohya, K., Tamura, S., Ichihara, M., Miyajima, A.and Senba, E.: "Expression of IL-6R, LIFR, and gp130 in murine cerebellum and neuropathologic effect of LIF to cerebellar Purkinje cells."Neuroscience. 100. 841-848 (2000)
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[Publications] Hayashi, M., Ueyama, T., Nemoto, K., Tamaki, T.and Senba, E.: "Sequential mRNA expression for immediate early genes, cytokines, and neurotrophins in spinal cord injury."J.Neurotrauma. 17. 203-217 (2000)
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[Publications] Kojima, T., Morikawa, Y., Copeland, N.G., Gilbert, D.J., Jenkins, N.A., Senba, E., Kitamura, T.: "TROY, a newly identified member of the tumor necrosis factor receptor superfamily, exhibits a homology with Edar and is expressed in embryonic skin and hair follicles."J.Biol.Chem.. 275. 20742-20747 (2000)
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