2002 Fiscal Year Final Research Report Summary
Cloning of cDNA candidates enforcing brain-specific entry in microglia
| Project/Area Number |
13680854
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Neurochemistry/Neuropharmacology
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| Research Institution | Fujita Health University |
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Principal Investigator |
SAWADA Makoto Fujita Health Univ., Inst. For Comprehensive Med. Sci., JRDTAID, Professor, 総合医科学研究所, 教授 (10187297)
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| Project Period (FY) |
2001 – 2002
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| Keywords | Microglia / gene transformation / brain-specific / drug delivery system / pharge display / blood-brain barrier |
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| Research Abstract |
The ability to manipulate the expression of genes within the mammalian brain provide unique opportunities to study and potentially treat neurologic disorders. To express certain genes specifically in brain has been done with viral vectors or cells carrying DNA, however, they all needed a surgical operation. Recently we found that microglia could enter specifically in brain when injected intra-arterially, and demonstrated that intra-arterial injection of microglia transfected with the lacZ gene resulted in expression of b-galactosidase up to three weeks post-injection in rat brain. This method will allow us to easily deliver the gene of interest to brain without any effects to other organs. In the present study, we compared migration of systemically injected microglia into normal brain vs. ischaemic brain using a model of ischaemic hippocampal lesion. Microglia were labeled by a fluorescent dye using our standard phagocytosis procedure of microscopic particles and then injected intra- arterially into Mongolian gerbils subjected to ischaemia reperfusion neuronal injury. Delayed death of pyramidal neurons was confirmed by conventional histological analysis and dUTP nick end labeling (TUNEL) method. Clusters of dye-tagged cells migrating into the hippocampal ischaemic lesions were confirmed histochemically to be microglia. Since peripherally injected microglia exhibit specific affinity for ischaemic brain lesions and does not exacerbate ischaemic neuronal injury in the present model, we suggest that microglia may have a potential to be used as a piggy-back ride to deliver therapeutic genes and/or drugs for CNS repair following transitory global ischaemic insult. Now we are trying to isolate gene(s) which product(s) are responsible for brain-specific entry of microglia by pharge-display screening system.
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[Publications] Salimi, K., Moser, K., Zassler, B., Reindl, M., Embacher, N., Schemer, C., Weis, C., Marksteiner, J., Sawada, M., Humpel, C: "Glial cell line-derived neurotrophic factor enhances survival of GM-CSF dependent rat GMIR1-microglial cells"Neurosci. Res.. 43. 221-229 (2002)
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