遺伝性神経変性疾患におけるトリプレットリピート伸張

• Project/Area Number: 09044357
• Research Category: Grant-in-Aid for international Scientific Research
• Allocation Type: Single-year Grants
• Section: Joint Research
• Research Field: Human genetics
• Research Institution: National Research Institute for Child Health and Development
• Principal Investigator: 山田 正夫 国立小児病院, 小児医療研究センター先天異常研究部, 部長 (40124218)
• Co-Investigator(Kenkyū-buntansha): POTTER Nich University of Tennessee Medical Center, Assistant ; BURKE James Duke University Medical Center, Division, Assistant ; 奥山 虎之 国立小児病院, 奇形研究室, 室長 ; 宮下 俊之 国立小児病院, 遺伝染色体研究室, 室長 (60174182) ; POTTER Nicho University of Tennessee Medical Center, Assistant
• Project Period (FY): 1997 – 1998
• Project Status: Completed (Fiscal Year 1998)
• Budget Amount: ¥3,800,000 (Direct Cost: ¥3,800,000); Fiscal Year 1998: ¥1,800,000 (Direct Cost: ¥1,800,000); Fiscal Year 1997: ¥2,000,000 (Direct Cost: ¥2,000,000)
• Keywords: トリプレットリピート伸長病 / ポリグルタミン / アポトーシス / 歯状核赤核淡蒼球ルイ体萎縮症 / DRPLA / ハンチントン舞踏病 / 遺伝病 / 神経変性疾患 / トリプレットリピート / プロモーター

Research Abstract

1. 臨床症状からハンチントン舞踏病と診断されていたが、HD遺伝子のCAGリピートの伸張を伴っていなかった米国の患者についてDNAを検査し、7家系11名でDRPLAと同定した。またユダヤ人で中間体リピートを検出した。これらの家系DNAについて、山田の研究室でハプ口タイプを解析し、起源などを明らかにした。
2. CAGリピート伸張病における神経細胞死の機構について、凝集体形成およびアポトーシスの関与が指摘されつつある。この方面の研究情報を交換し、それぞれの研究室の最新結果を交換するなどして、神経細胞死機構の研究を進めた。特に微小凝集体(あるいは凝集性)が重要な鍵であること、またCaspase-8の早期の関与を明らかにでき、この分野の迅速な発展に大きく貢献した。

Research Products

• [Publications] Miyashita,T.: "Intracellular aggregate formation of dentatorubral-pallidoluysian atrphy(DRPLA)protein with the extended polyglutamine." Biochemical and Biophysical Research Communications. 249(1). 96-102 (1998)
• [Publications] Miyashita,T.: "Investigation of glucocorticoid-induced apoptotic pathway:processing of caspase-6 but not caspase-3." Cell Death and Differentiation. 5(12). 1034-1041 (1998)
• [Publications] Takayama,S.: "Expression and location of Hsp70/Hsc-binding anti-apoptotic protein BAG-1 and its variants in normal tissues tumor cell lines." Cancer Research. 58(14). 3116-3131 (1998)
• [Publications] Okuyama,T.: "Efficent Fas-ligand gene expression in rodent liver after intravenous injection of a recombinant adenovirus by the use of a Cre-mediated switching system." Gene Therapy. 5(8). 1047-1053 (1998)
• [Publications] Okuyama,T.: "Fas-mediated apoptosis is involved in the elimination of gene-transduced hepatocytoes with E1/E3-deleted adenoviral vectors." Journal of Gastroenterology and Hepatology. 13(suppl.). S113-118 (1998)
• [Publications] Okuyama,T.: "Hepatocyte-specific gene expression by a recombinant adeno-associated virus vector carrying apolipooprotein E enhancer and α1-antitrypsin promoter." Gene Therapy and Molecular Biology. 3. 67-74 (1998)
• [Publications] Li,X-K.: "Prolonged survival of rat liver allografts transfected with Fas ligand-expressing plasmid." Transplantation. 66(11). 1416-1423 (1998)
• [Publications] Azuma,N.: "Missense mutation at the C terminus of the PAX6 gene in ocular anterior segment anomalies." Investigative Ophthalmology and Visual Science. 39(5). 828-830 (1998)
• [Publications] Azuma,N.: "Missense Mutations in the PAX6 gene in aniridia." Investigative Ophthalmology and Visual Science. 39(13). 2524-2528 (1998)
• [Publications] Yuan,ZR.: "Mutational analysis of the Jagged 1 gene in Alagille syndrome families." Human Molecular Genetics. 7(9). 1363-1369 (1998)
• [Publications] Sakai,K.: "The genomic organization of the human corticotropin-releasing factor type-1 receptor." Gene. 219(1-2). 125-130 (1998)
• [Publications] Azuma, N., et al.: "Missense mutation at the C-terminal of the PAX6 gene in ocular anterior segment anomalies." Invest.Ophthalmol.Vis.Sci.(in press).
• [Publications] Okuyama, T., et al.: "Fas mediated apoptosis is involved in the elimination of gene-transduced hepatocytes with E1/E3-deleted abdenoviral vectors." J.Gastroenterol.Hepatol.(in press).
• [Publications] Miyashita, T., et al.: "Dentatorubral pallidoluyaian atrophy (DRPLA)protein is cleaved by caspase-3 during apoptosis." J.Biol.Chem.272. 29238-29242 (1997)
• [Publications] Yamaguchi, Y., et al.: "Autoregulation of Pax6 transcriptional activation by two distinct DNA-binding subdomains of the paired domain." Genes Cells. 2. 255-261 (1997)
• [Publications] Nishiyama, K., et al.: "Regional and cellular expression of the dentatorubral-pallidoluysian atrophy gene in brains of normal and affected individuals." Ann.Neurol.41. 599-605 (1997)
• [Publications] Miyashita, T., etal.: "Bcl-2 relieves the trans-repressive function of the glucocorticoid receptor and inhibits the sctivation of CPP32-like cysteine proteases." Biochem.Biophys.Res.Commun.233. 781-787 (1997)