| Project/Area Number |
14370211
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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 |
Neurology
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| Research Institution | Juntendo University |
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Principal Investigator |
MOCHIZUKI Hideki Juntendo University, Dept. of Neurology, Assistant professor, 医学部, 講師 (90230044)
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| Co-Investigator(Kenkyū-buntansha) |
水野 美邦 順天堂大学, 医学部, 教授 (30049043)
島田 隆 日本医科大学, 医学部, 教授 (20125074)
卜部 貴夫 順天堂大学, 医学部, 講師 (60291663)
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| Project Period (FY) |
2002 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥13,900,000 (Direct Cost: ¥13,900,000)
Fiscal Year 2003: ¥6,700,000 (Direct Cost: ¥6,700,000)
Fiscal Year 2002: ¥7,200,000 (Direct Cost: ¥7,200,000)
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| Keywords | Parkinson's disease / Gene therapy / AAV vector / Caspase 11 / Apaf-1-DN / MPTP / アデノ随伴ウイルスベクター / α-synuclein / 猿 / Apaf-1-DN / 大型動物(猿) / Apaf-1 / alpha-synuclein / アポトーシス |
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| Research Abstract |
Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease. In this report, we focused on the pathogenesis and treatment of PD.
The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes a parkinsonian syndrome in humans and primates after selective uptake of its metabolite, MPP^+, into dopaminergic neurons. We sought to determine the major pathway of MPTP toxicity from among several apoptotic pathways. We already established in vivo models of the inhibition of caspase cascade using adeno-asociated virus (AAV) vectors. We showed persistent high levels of focal Apaf-1 CARD or caspase-1 C285G mutant expression were available for further in vivo studies and for possible anti-apoptotic gene therapy in patients with PD. In this report, we confirm the effect and the safe of AAV vector using the primates for the clinical trial. AAV vector, a single-strand DNA virus from the parvovirus family, has become one of the most promising vectors for the introduction of the gene of interest into neurons (Mochizuki et al.2001). With regard to safety issues, the genetically modified primate model is simple and safe since the AAV is a non-pathogenic virus. Furthermore, we have already established the procedure for preparing parkinsonian rat and mice models that overexpress mutated α-synuclein using the AAV vector system. Thus, by stereotactically injecting AAV-mutated α-synuclein in the substantia nigra of monkeys; we established a genetically modified primate model with overt hemiparkinsonism in Tukuba primate center. Further analysis will be performed. (240)
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