Studies on Molecular Mechanisms underlying Neural Cell Death in Neural Differentiation and Degenerative Disease.
| Project/Area Number |
14580730
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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 |
Nerve anatomy/Neuropathology
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| Research Institution | Nagahama Institute of Bio-Science and Technology (2004-2005)
Osaka University (2002-2003) |
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Principal Investigator |
UETSUKI Taichi Nagahama Institute of Bio-Science and Technology, Cell Biology, Professor, バイオサイエンス学部, 教授 (20260309)
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| Project Period (FY) |
2002 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2005: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2004: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2003: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2002: ¥900,000 (Direct Cost: ¥900,000)
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| Keywords | Neuron / Alzheimer Disease / Neural Degeneration / Apoptosis / Prader-Willi Syndrome / Necdin / Knock-out mice / Amyloid Precursor Protein / 遺伝子導入ベクター / バキュウロウイルスベクター / プラダーウィリー症候群 / バキュロウイルスベクター / アデノウイルスベクター / E2F1 / 遺伝子治療 / 神経発生 / カスパーゼ |
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| Research Abstract |
This research work was composed of two major projects. One is to elucidate the pathological implications of intracellular accumulation of the amyloid precursor protein (APP) in postmitotic neurons. Another is to study the functions of Necdin and link between Necdin and Prader-Willi syndrome by generating Necdin-deficient mice.
We have reported that accumulation of full length APP may be the main cause of apoptosis-like neurodegeneration, and degenerating neurons contained activated caspase-3, and prior to the apoptotic change became apparent, activity of Caspase-3 was increased. In this project, various mutated APP was produced to determine the domains in APP molecule involving in the neurodegeneration. As results, we demonstrated that accumulation of wild-type APP activates neuronal casapase-3 to generate APP with 31 Amino acids truncated carboxyl terminus. We also investigated the molecular pathways underlying APP-induced neural degeneration. Overexpression of APP significantly increa
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sed intracellular Ca^<2+> content and activation of calpain, a Ca^<2+>-dependent cysteine protease was observed prior to the caspase-3 activation. Calpain inhibitors alomost completely suppressed APP-induced activation of neuronal caspase-3. These results suggest that overexpression of wild-type APP activates calpain that mediates caspase-3 activation in postmitotic neurons. Necdin is a multifunctional signaling protein that stabilizes terminal differentiation of postmitotic neurons. To elucidate the Necdin functions in vivo, and the link between the functions and symptoms of Prader-Willi syndrome, we generate the Necdin deficient mice. In mice lacking the paternal Necdin allele displayed augmented apoptosis in the sensory ganglia in vivo and had a reduced population of substance P-containing neurons. And in the necdin-null sensory ganglia, NGF-induced phosphorylation of TrkA and mitogen-activated protein kinase was significantly diminished. Mutant mice showed significantly high tolerance the thermal pain which is often seen in individuals with Prader-Willi syndrome. These results suggest that Necdin facilitates TrkA signaling to promote the survival of NGF-dependent nociceptive neurons. Less
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Report
(5 results)
Research Products
(12 results)
