1997 Fiscal Year Annual Research Report

炎症性増殖性血管病変の分子病態解明と遺伝子治療法の開発 -組換えアデノウィルスを用いた血管壁・心臓への生体内遺伝子導入による病態解析と治療効果の検討-

Research Project

Project/Area Number	09470170
Research Institution	Kyushu University
Principal Investigator	上野光九州大学, 医学部, 講師 (50260378)
Co-Investigator(Kenkyū-buntansha)	居石克夫九州大学, 医学部, 教授 (70108710) 盛栄三東海大学, 医学部, 助教授 (90146598) 西田誉浩九州大学, 医学部, 助手 (50284500) 大原郁一九州大学, 医学部, 助手 (90185364) 筒井裕之九州大学, 医学部, 講師 (70264017)
Keywords	組換えアデノウイルス / 遺伝子治療 / 再狭窄 / 血管新生 / TGF-b / H-ras / TFPI / FGF
Research Abstract	1.機能抑制型H-Ras(D/N Ras)、細胞周期進行を抑制するCyclin-dependent kinase Inhibitor-p21WAF1/Sdilを発現するアデノウイルスを作製し、血管平滑筋細胞に導入すると血清増殖因子による平滑筋細胞のDNA合成は完全に抑制された。バルーンで傷害を加えたラット頚動脈に導入したところ、新生内膜肥厚を有意に抑制することに成功した(2論文発表)。 2.C-type natriuretic peptideをアデノウイルスを用いてラット傷害頚動脈に導入すると内膜肥厚はほぼ完全に抑制された。強力な細胞増殖抑制作用は必須ではないこと、パラクライン作用を持つ分子が有用であることが示された(論文発表)。 3.細胞内のキナーゼ部分を欠失した変異型のTGF-βII型受容体発現アデノウイルス(TGF-βの作用を特異的に抑制できる)を実験線維症モデルに導入したところ線維化が抑制され、線維化におけるTGF-βの中心的動的役割を証明するとともに新しい治療の可能性を開拓した(4論文投稿中)。 4.TGF-βの細胞内信号伝達におけるRas,Racの役割を解析した(論文投稿中)。 5.血管新生因子であるFGF(Fibroblast growth factor)産生アデノウイルスを作製し、マウス皮下での血管新生を確認した(論文発表)。血管新生療法をめざして虚血心筋への導入実験を開始した。 6.凝固反応の開始因子である組織因子の特異的抑制分子(Tissue factor athway inhibitor:TFPI)遺伝子を傷害血管壁に導入するとShear stressによる血栓形成は完全に抑制され、その抑制はカテコラミン負荷でも影響を受けなかった。全身の凝固線溶系には全く影響を与えず、血栓症への遺伝子治療の可能性を示した(2論文投稿中)。

Research Products
(11 results)

All Other

All Publications (11 results)

[Publications] Sakamoto T.,et al.: "Transfection of LacZ gene to retina by an adenoviral vector causes retinal dysfunction with no apparent morphological changes." Hum.Gene Ther.(in press).
[Publications] Takayama K.,et al: "The levels of integrin aV and b5 may well predict the susceptibility to adenovirus-mediated gene transfer in human lung cancer cells." Gene Ther.(in press).
[Publications] Li Q.,et al.: "Stretch-induced collagen syntesis in cultured smooth muscle cells from rabbit aortic media and possible involvement of angiotensin II and TGF-b." Vasc.Res.(in press).
[Publications] Ueno H.,et al.: "Adenovirus-mediated expression of secreted form of basic fibroblast growth factor(FGF-2)induces cellular proliferation and angiogenesis in vivo." Arterioscl.Thromb.Vasc.Biol.17. 2453-2460 (1997)
[Publications] Ueno H.,et al.: "Adenovirus-mediated transfer of a dominant-negative H-ras suppresses neointimal formation in balloon-injured arteries in vivo.Arterioscl." Thromb.Vasc.Biol.17. 898-904 (1997)
[Publications] Ueno H.,et al: "Local expression of C-type natriuretic peptide markedly suppresses neointimal formation in rat injured arteries through an autocrine/paracrine loop." Circulation. 96. 2272-2279 (1997)
[Publications] Ueno H.,et al: "Adenovirus-mediated transfer of cyclin-dependent kinase inhibitor-p21 suppresses neointimal hyperplasia in balloon-injured arteries in vivo." Ann.NY Acad.Sci.811. 401-411 (1997)
[Publications] Takahashi T.,et al.: "Angiotensin II stimulates mitogen-activated protein kinases ans protein synthesis by a rasindependent pathway in vascular smooth muscle cells." J.Biol.Chem.272. 16018-16022 (1997)
[Publications] Kitamura Y.,et al.: "Interaction of Nck-associated protein 1 with activatied GTP-binding protein" Rac.Biochem.J.3332. 873-878 (1997)
[Publications] Sakaue H.,et al.: "Phosphoinositide 3-kinase is required for insulin-induced but not for growth hormone-or hyperosmolarity-induced glucose uptake in 3T3-L1 adipocytes." Mol.Endocrinol.11. 1551-1562 (1997)
[Publications] Li Q.,et al.: "Stretch-induced proliferation of cultured vascular smooth muscle cells and possible involvement of local renin-angiotensin system and platelet-derived growth factor." Hypertens.Res.20. 217-223 (1997)

1997 Fiscal Year Annual Research Report

炎症性増殖性血管病変の分子病態解明と遺伝子治療法の開発 -組換えアデノウィルスを用いた血管壁・心臓への生体内遺伝子導入による病態解析と治療効果の検討-

Principal Investigator

上野 光 九州大学, 医学部, 講師 (50260378)

Research Products

[Publications] Sakamoto T.,et al.: "Transfection of LacZ gene to retina by an adenoviral vector causes retinal dysfunction with no apparent morphological changes." Hum.Gene Ther.(in press).

[Publications] Takayama K.,et al: "The levels of integrin aV and b5 may well predict the susceptibility to adenovirus-mediated gene transfer in human lung cancer cells." Gene Ther.(in press).

[Publications] Li Q.,et al.: "Stretch-induced collagen syntesis in cultured smooth muscle cells from rabbit aortic media and possible involvement of angiotensin II and TGF-b." Vasc.Res.(in press).

[Publications] Ueno H.,et al.: "Adenovirus-mediated expression of secreted form of basic fibroblast growth factor(FGF-2)induces cellular proliferation and angiogenesis in vivo." Arterioscl.Thromb.Vasc.Biol.17. 2453-2460 (1997)

[Publications] Ueno H.,et al.: "Adenovirus-mediated transfer of a dominant-negative H-ras suppresses neointimal formation in balloon-injured arteries in vivo.Arterioscl." Thromb.Vasc.Biol.17. 898-904 (1997)

[Publications] Ueno H.,et al: "Local expression of C-type natriuretic peptide markedly suppresses neointimal formation in rat injured arteries through an autocrine/paracrine loop." Circulation. 96. 2272-2279 (1997)

[Publications] Ueno H.,et al: "Adenovirus-mediated transfer of cyclin-dependent kinase inhibitor-p21 suppresses neointimal hyperplasia in balloon-injured arteries in vivo." Ann.NY Acad.Sci.811. 401-411 (1997)

[Publications] Takahashi T.,et al.: "Angiotensin II stimulates mitogen-activated protein kinases ans protein synthesis by a rasindependent pathway in vascular smooth muscle cells." J.Biol.Chem.272. 16018-16022 (1997)

[Publications] Kitamura Y.,et al.: "Interaction of Nck-associated protein 1 with activatied GTP-binding protein" Rac.Biochem.J.3332. 873-878 (1997)

[Publications] Sakaue H.,et al.: "Phosphoinositide 3-kinase is required for insulin-induced but not for growth hormone-or hyperosmolarity-induced glucose uptake in 3T3-L1 adipocytes." Mol.Endocrinol.11. 1551-1562 (1997)

[Publications] Li Q.,et al.: "Stretch-induced proliferation of cultured vascular smooth muscle cells and possible involvement of local renin-angiotensin system and platelet-derived growth factor." Hypertens.Res.20. 217-223 (1997)

上野光九州大学, 医学部, 講師 (50260378)