ESTABLISHMENT OF A RAT STRATIN WITH MUCOPOLYSUCCHARIDOSIS TYPE VI AS AN ANIMAL MODEL FOR GENE THERAPY

粘多糖症VI型大鼠模型的建立作为基因治疗的动物模型

• 批准号: 07558240
• 负责人: KUNIEDA Tetsuo
• 金额: $ 1.22万
• 依托单位: OKAYAMA UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 1996
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07558240/
• 关键词: RATS; ANIMAL MODEL; MUCOPOLYSUCCHARIDOSIS; LYSOSOME; ARYLSULFATASE; MUTATION; SOMATIC-CELL HYBRIDS; MAPPING; ワソゾーム

The present research project was carried out to establish the MPR rat as an animal model for human hereditary mucopolysuccharidosis type VI by identifying the mutation responsible for the phenotypes and by examinating therapeutic effects of bone marrow transplantation.We compaired the nucleotide sequences of the rat arylsulfatase B gene by cloning nad sequencing the gene, and found an insertional mutation that causes a fram-shift of the gene. We further revealed that an amplification of the region including the mutation enables to easily identify carriar rats of the mutation.We performed bone marrow transplantation to confirm therapeutic effects of supplement of the normal enzyme producing cells. The recipient rats showed no accumulation of glycosaminoglycan in organs and no urinary excretion of the glycosaminoglycan but partial resoluation of facial dysmorphia and bony feutures, indicating therapeutic effects of the bone marrow transplantation.We, therefore, concluded that the MPR rat is a useful animal model for mucopolysaccharidosis type VI of human.

本研究旨在通过鉴定引起表型突变的基因突变和检测骨髓移植的治疗效果，建立人类遗传性粘多糖病VI型的动物模型。通过克隆和测序，比较大鼠芳基硫酸酯酶B基因的核苷酸序列，发现一个插入突变，导致该基因的帧移位。我们进一步发现，包括突变在内的区域的扩增能够很容易地识别突变的Carriar大鼠。我们进行了骨髓移植，以确认补充正常产酶细胞的治疗效果。移植组大鼠各脏器未见糖胺多糖蓄积，尿液中未见糖胺多糖排泄，但面部畸形和骨缺损处部分消退，表明骨髓移植有一定的治疗作用。因此，MPR大鼠是一种较好的人类VI型粘多糖病动物模型。

项目成果

R.Valdivia et al: "Typing of X chromosome bearing Tabby allele in ・・・・" Eyp.Anim. 45. 395-398 (1996)

R.Valdivia 等人：“带有虎斑等位基因的 X 染色体的分型……”Eyp.Anim. 45. 395-398 (1996)

Kunieda, T., Kobayashi, E., Tachibana, M., Ikadai, H.: "Localizaion of a Moloney murine leukemia virus integration site gene, M1vi2, on rat chromosome 2." Mamm.Genom.7. 924-925 (1996)

Kunieda, T.、Kobayashi, E.、Tachibana, M.、Ikadai, H.：“莫洛尼鼠白血病病毒整合位点基因 M1vi2 在大鼠 2 号染色体上的定位。”

Yoshida M,Barata K,Takahashi M Ando-Lu J and Maekawa A.: "A case report of superficial necrolytic dermatitis in a beagle dog with diabetes mellitus." Toxicol.Pathol.24. 498-501 (1996)

Yoshida M、Barata K、Takahashi M、Ando-Lu J 和 Maekawa A.：“患有糖尿病的比格犬浅表坏死性松解性皮炎的病例报告。”

Kobayashi, E., Tachibana, M., Ikadai, H., and kunieda, T.: "Localization of Na^+, K^+-ATPase a 2 subunit gene, ATP1A2, on rat chromosome 13." Mamm.Genom. 6. 889 (1995)

Kobayashi, E.、Tachibana, M.、Ikadai, H. 和 kunieda, T.：“Na^ 、K^ -ATPase a 2 亚基基因 ATP1A2 在大鼠 13 号染色体上的定位。”

Kunieda, T: "Mucopolysacchridosis Type VI in Rats." Genomics. 29. 582-587 (1995)

Kunieda, T：“大鼠粘多糖病 VI 型。”