| Project/Area Number |
17500289
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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 |
Laboratory animal science
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| Research Institution | Kitasato University |
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Principal Investigator |
FURUDATE Sen-ichi Kitasato University, School of Medicine, Associate Professor (80095512)
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| Co-Investigator(Kenkyū-buntansha) |
SAKAI Yasuhiiro Kitasato university, School of Medicine, Associate Professor (00050625)
AZUMA Sadahiro Kitasato university, School of Medicine, Research Associate (80348507)
SUZUKI Nobuyuki Kitasato university, School of Applied Health Sciences, Associate Professor (10050650)
OH-ISHI Masamichi Kitasato university, School of Science, Assistant Professor (40233027)
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| Project Period (FY) |
2005 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥300,000)
Fiscal Year 2007: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2006: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2005: ¥1,200,000 (Direct Cost: ¥1,200,000)
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| Keywords | rdw / congenital hypothyroidism / non-goiter / ancreatic uroteome / dopamine D_2-like receptor / thyroid hormone / mutant Tg-ERp72 interaction / molecular chaperon / NMDA recptor / NR1 / NR2 / リン酸化 / 脳 / クレチン症 / モデル動物 / 小脳 / 甲状腺機能低下症 / thyroglobulin / non-goiter / Tpo / ERp72 / 神経 / 大脳皮質 / 海馬 / ドーパミンD2受容体 / CNPase |
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| Research Abstract |
A mutation in the Thyroglobulin (Tg) gene (Tg-G2320R) is the primary cause of hereditary dwarfism and hypothyroidism in the rdw rat.
1) Elastase and lipase reduced in pancreatic proteome and those proteins recovered by thyroxine injection or thyroid graft. 2) The Tg-G2320R mutation is responsible for congenital hypothyroidism in rdw rats, in which a lack of secondary thyroid enlargement (goiter) implicates death of thyrocytes as part of desease pathogenesis. We found that mutant Tg-G2320R was retained within the ER with no detectable synthesis of thyroxine, had persistent exposure of free chiols, and was associated with activated ER stress response but incomplete ER associated degradation (ERAD). Tg-G2320R associated with multiple ER resident proteins, most notably ERp72, including covalent Tg-ERp72 interactions. In PC C13 thyrocytes, inducible overexpression of ERp72 increased the ability of cells to maintain Tg cysteines in a reduced state. Non covalent interactions of several ER chaperones with newly synthesized Tg-G2320R diminished over time in paralled with ERAD of the mutant protein, yet a small ERAD-resistant Tg fraction remained engaged in covalent association with ERp72 even 2 days post-synthesis. Such covalent protein aggregates may set the stage for apoptotic thyrocyte cell death, preventing thyroid, goiter formation in rdw rats. 3) Dopamine D2-like receptor function is converted from excitatory to inhibitory by thyroxine in the developmental hippocampus using rdw rats having deficient thyroid hormone. 4) The infertility of rdw male rats was recovered by thyroid graft.
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