| Project/Area Number |
10670603
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Neurology
|
|---|
| Research Institution | JUNTENDO UNIVERSITY |
|---|
Principal Investigator |
MIZUNO Yoshikuni (1999-2000) Juntendo Univ.Dept.of Neurology, Professor, 医学部, 教授 (30049043)
田久保 秀樹 (1998) 順天堂大学, 医学部, 講師 (90163360)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
MOCHIZUKI Hideki Juntendo Univ.Dept.of Neurology, Assistant Professor, 医学部, 講師 (90230044)
水野 美邦 順天堂大学, 医学部, 教授 (30049043)
|
|---|
| Project Period (FY) |
1998 – 2000
|
| Project Status |
Completed (Fiscal Year 2000)
|
| Budget Amount *help |
¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 2000: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 1999: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 1998: ¥1,600,000 (Direct Cost: ¥1,600,000)
|
|---|
| Keywords | neurotoxin / Parkinson's disease / Caspase-11 / NF-kB / MPTP / Knock out mouse / ノックアウトマウス / カスパーゼ1 / カスパーゼ11 / MnSOD / アポトーシス / アデノウイルス / フリーラジカル / 本年度の研究実施計画 / ミトコンドリア / パパベリン / ヅメトキツフェニルエチルアミン / ドパミン |
|---|
| Research Abstract |
The neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahy-dropyridine (MPTP) causes a parkinsonian syndrome in humans and primates after selective uptake of its metabolite MPP + into dopaminergic neurons. MPP + is concentrated into mitochondria down the electrochemical gradient, and selectively and potently inhibits complex-I of the electron transport chain. Sporadic Parkinson's disease (PD) is characterized by oxidative stress and specifically involves a defect in complex I of the electron transport chain. To identift the mechanism of PD, we explore the possible involvement of the MPTP in PD models
Recently, Dr.Hunt showed the upregulation of the nuclear translocation of NF-kB in the postmortem Parkinsonian brain. To identify the role of NF-kB, we regulated its intranuclear translocation by overexpression of Ik-B.A super repressor IkB has serine-to-alanine mutations in residues 32 and 36, which inhibit its phosphorylation. We used adenovirus to overexpress the supper repressor IkB gene into the neuron. Ad-Ik-B treatment significantly decreased the ratio of MPP+ induced cell death compared with the ratio of MPP+ induced cell death treated with a Mock infection.
The cascade involving caspase 1 and caspase 11 may be one of the common pathways for neuronal cell death in pathological condition. We stereotactically injected MPTP into the striatum of caspase 11 KO mice. This shows TH staining of the mice. This picture is a MPTP untreated caspase 11 KO mouse. This picture is a MPTP treated normal mouse. This picture is a MPTP treated caspase 11 KO mouse. Caspase 11 KO mice prevent the cell death of MPTP.
|
