Grant-in-Aid for COE Research
|Allocation Type||Single-year Grants |
|Research Institution||Nagoya University |
TAKAHASHI Masahide Graduate School of Medicine, Professor, 大学院・医学系研究科, 教授 (40183446)
FURUKAWA Koichi Graduate School of Medicine, Professor, 大学院・医学系研究科, 教授 (80211530)
SOBUE Gen Graduate School of Medicine, Professor, 大学院・医学系研究科, 教授 (20148315)
MURAMATSU Takashi Graduate School of Medicine, Professor, 大学院・医学系研究科, 教授 (00030891)
HAMAGUCHI Michinari Graduate School of Medicine, Professor, 大学院・医学系研究科, 教授 (90135351)
|Project Period (FY)
1998 – 2002
Completed(Fiscal Year 2002)
|Budget Amount *help
¥1,113,800,000 (Direct Cost : ¥1,046,000,000、Indirect Cost : ¥67,800,000)
Fiscal Year 2002 : ¥293,800,000 (Direct Cost : ¥226,000,000、Indirect Cost : ¥67,800,000)
Fiscal Year 2001 : ¥210,000,000 (Direct Cost : ¥210,000,000)
Fiscal Year 2000 : ¥220,000,000 (Direct Cost : ¥220,000,000)
Fiscal Year 1999 : ¥210,000,000 (Direct Cost : ¥210,000,000)
Fiscal Year 1998 : ¥180,000,000 (Direct Cost : ¥180,000,000)
|Keywords||Neurodegenerative disease / Malignant tumor / RET gene / Midkine / Dorfin gene / Ganglioside / Cancer invasion / Transgenic mouse / 糖鎖合成酵素遺伝子 / Src遺伝子 / 浸潤・転移 / ノックアウトマウス / 癌転移 / 神経栄養因子|
1. To investigate the role of tyrosine 1062 in RET in neuronal differentiation, we produced knock-in mice in which tyrosine 1062 was replaced with phenylalanine. Differentiation of enteric neurons in the whole intestinal tract was severely impaired in mice, indicating that the intracellular signaling via tyrosine 1062 plays an important role in the development of the enteric nervous system.
2. The midkine (MK) receptor is thought to be a molecular complex of protepglycans including protein tyrosine phosphatase ζ (PTPζ) and syndecan. MK binds to the chondroitin sulfate portion of PTPζ, especially to the E unit that has 4,6-disulfated N-acetylgalactosamine, with high affinity. The binding of MK to syodecan was mediated by the trisulfated structure of N- and 6-O-sulfated glucosamine and 2-sulfated uronic acid.
3. Dorfin, a RING finger-type E3 ubiquitin ligase, is predominantly localized in the inclusion bodies of familial ALS with a copper/zinc superoxide dismutase (SOD1) mutation as well a
s sporadic ALS. Dorphin physiologically bound and ubiquitylated various SOD1 mutants derived from familial ALS patients and enhanced their degradation. The overexpression of Dorfin protected against the toxic effects of mutant SOD1 on neural cells and reduced SOD1 inclusions.
4. Double knock-out mice lacking the GM2/GD2 and the GD3 synthase gene were generated by mating single gene mutants. We observed a refractory skin lesion that appeared on the face of mutant mice at 25 weeks after birth or later. Characteristic proliferation of nerve fibers was found in the epidermis and subepidermis at the injured sites, probably a result of continuous skin injury. Peripheral nerve degeneration was observed in young mutant mice, suggesting that reduced sensory function induced over-scratching.
5. Treatment of QG90 human lung cancer cells with hyaluronan (HA) strongly activated MMP-2 secretion and expression of antisense CD44s in QG90 cells inhibited the HA-dependent secretion of MMP-2. We found that HA-CD44 signaling plays a key role in the HA-dependent secretion of MMP-2 and, hence, in the invasiveness of QG90 cells. Less