2000 Fiscal Year Annual Research Report

生体内遺伝子導入による難治性血管病の分子病態解明と局所遺伝子療法の開発

Research Project

Project/Area Number	12470157
Research Institution	University of Occupational and Environmental Health, Japan
Principal Investigator	上野光産業医科大学, 医学部, 教授 (50260378)
Co-Investigator(Kenkyū-buntansha)	笹栗靖之産業医科大学, 医学部, 教授 (60140646) 松田武久九州大学, 大学院・医学系研究科, 教授 (60142189) 濱田洋文札幌医科大学, 医学部, 教授 (00189614)
Keywords	血栓症 / 遺伝子治療 / TFPI / CNP / TGF-β / 再狭窄 / 傷害血管 / 人工血管
Research Abstract	生体内遺伝子導入法を用いて傷害血管壁における炎症性増殖性病変の分子病態解明と新規治療法の開発を目的とする。今年度は、 (i)血管壁に傷害が加わった時最初に起る反応である血栓を抑制するために、組織因子の生理的拮抗分子であるTFPI(Tissue factor pathway inhibitor)に着目した。遺伝子導入では傷害直後の血栓を抑制できないため、組換え蛋白と遺伝子導入の併用療法の有用性を検証した。組換えTFPI蛋白を病変局所に20分間灌流すると24時間後でも傷害血管壁の組織因子活性は抑制されていた。24時間以降は遺伝子導入したTFPIの効果が出現した。それぞれ単独でも内膜肥厚を抑制したが、両者を併用すると相加効果が認められた。組換えTFPI蛋白と遺伝子導入の併用は実用的な抗血栓戦略である。 (ii)TFPIやCNP(C-type natriuretic peptide)遺伝子を導入した線維芽細胞と生体材料を複合したハイブリッド型細小人工血管では抗血栓性が出現した。 (Iii)CNP遺伝子を針付きカテーテルで経管的にブタ冠動脈に導入すると傷害後の内膜肥厚が有意に抑制された。 (iv)細胞外マトリクス蓄積が内腔狭窄と血管弛緩機能喪失の大きな原因である可能性がある。細胞外マトリクス産生を抑制するため細胞内キナーゼ活性を欠失した変異型TGF-受容体(野生型受容体機能を抑制)、さらに細胞外領域のみの可溶型受容体を作製し、その有用性を肝線維症モデル他で確認した。来年度は傷害血管壁における線維化の意義を検討する。

Research Products

(14 results)

All Other

All Publications (14 results)

[Publications] Atsuchi N.: "Combination of a brief irrigation with tissue factor pathway inhibitor (TFPI) and adenovirus-mediated local TFPI gene transfer additively reduces neointima formation in balloon-injured rabbit carotid arteries."Circulation. 103. 570-575 (2001)
[Publications] Morishige K.: "Local adnovirus-mediated transfer of C-type natriuretic peptide suppresses vascular remodeling in porcine coronary arteries in vivo."J.Am.Coll.Cardiol.. 35. 1040-1047 (2000)
[Publications] Tanaka E.: "Amelioration of microvascular myocardial ischemia by gene transfer of vascular endothelial growth factor in rabbits."J Thorac Cardiov Sur. 120. 720-728 (2000)
[Publications] Hirashima Y.: "Transfection of the plasma-type platelet-activating factor acethylhydrolase gene attenuates glutamate-induced apoptosis in cultured rat cortical neurons."Brain Res.. 885. 128-132 (2000)
[Publications] Iwatate M.: "Effects of in vivo gene transfer of FGF-2 on cardiac function and collateral vessel formation in microembolized rabbit heart."Jap.Circ.J.. (in press). (2001)
[Publications] Iwasaki H.: "Mechanical stretch stimulates growth of vascular smooth muscle cells via epidermal growth factor receptor."Am.J.Physiol.. 278. H521-H529 (2000)
[Publications] Masaki I.: "Recombinant Sendai Virus-mediated Gene Transfer to Vasculature : a new class of efficient gene transfer vector to the vascular system."FASEB J.. (in press). (2001)
[Publications] Nakamura T.: "Inhibition of Transforming Growth Factor-β prevents progression of liver fibrosis and enhances hepatocyte regeneration in dimethylnitrosamine-treated rats."Hepatology. 32. 247-255 (2000)
[Publications] Sakamoto T.: "Blockade of TGF-β by in vivo gene transfer of a soluble TGF-β type II receptor in the muscle inhibits corneal opacification, edema and angiogenesis."Gene Ther.. 7. 1915-1924 (2000)
[Publications] Ueno H.: "A soluble TGF-β receptor expressed in muscle prevents liver fibrogenesis and dysfunction in rats."Hum Gene Ther.. 11. 33-42 (2000)
[Publications] Takayama K.: "Suppression of tumor angiogenesis and growth by gene transfer of a soluble form of VEGF receptor into a remote organ."Cancer Res.. 60. 2169-2177
[Publications] Sato N.: "A possible role for centrosome overduplication in radiation-induced cell death."Oncogene. 19. 5281-5290
[Publications] Honda M.: "Adenovirus-mediated gene transfer of soluble flt-1 receptor inhibits the experimental subretinal neovasucularization."Gene Ther.. 7. 978-985 (2000)
[Publications] Shiose S.: "Gene transfer of a soluble receptor of VEGF inhibits the growth of experimental eyelid malignant melanoma."Invest.Ophthalmol.Vis.Sci.. 41. 2395-2403 (2000)

2000 Fiscal Year Annual Research Report

生体内遺伝子導入による難治性血管病の分子病態解明と局所遺伝子療法の開発

Principal Investigator

上野 光 産業医科大学, 医学部, 教授 (50260378)

Research Products

[Publications] Atsuchi N.: "Combination of a brief irrigation with tissue factor pathway inhibitor (TFPI) and adenovirus-mediated local TFPI gene transfer additively reduces neointima formation in balloon-injured rabbit carotid arteries."Circulation. 103. 570-575 (2001)

[Publications] Morishige K.: "Local adnovirus-mediated transfer of C-type natriuretic peptide suppresses vascular remodeling in porcine coronary arteries in vivo."J.Am.Coll.Cardiol.. 35. 1040-1047 (2000)

[Publications] Tanaka E.: "Amelioration of microvascular myocardial ischemia by gene transfer of vascular endothelial growth factor in rabbits."J Thorac Cardiov Sur. 120. 720-728 (2000)

[Publications] Hirashima Y.: "Transfection of the plasma-type platelet-activating factor acethylhydrolase gene attenuates glutamate-induced apoptosis in cultured rat cortical neurons."Brain Res.. 885. 128-132 (2000)

[Publications] Iwatate M.: "Effects of in vivo gene transfer of FGF-2 on cardiac function and collateral vessel formation in microembolized rabbit heart."Jap.Circ.J.. (in press). (2001)

[Publications] Iwasaki H.: "Mechanical stretch stimulates growth of vascular smooth muscle cells via epidermal growth factor receptor."Am.J.Physiol.. 278. H521-H529 (2000)

[Publications] Masaki I.: "Recombinant Sendai Virus-mediated Gene Transfer to Vasculature : a new class of efficient gene transfer vector to the vascular system."FASEB J.. (in press). (2001)

[Publications] Nakamura T.: "Inhibition of Transforming Growth Factor-β prevents progression of liver fibrosis and enhances hepatocyte regeneration in dimethylnitrosamine-treated rats."Hepatology. 32. 247-255 (2000)

[Publications] Sakamoto T.: "Blockade of TGF-β by in vivo gene transfer of a soluble TGF-β type II receptor in the muscle inhibits corneal opacification, edema and angiogenesis."Gene Ther.. 7. 1915-1924 (2000)

[Publications] Ueno H.: "A soluble TGF-β receptor expressed in muscle prevents liver fibrogenesis and dysfunction in rats."Hum Gene Ther.. 11. 33-42 (2000)

[Publications] Takayama K.: "Suppression of tumor angiogenesis and growth by gene transfer of a soluble form of VEGF receptor into a remote organ."Cancer Res.. 60. 2169-2177

[Publications] Sato N.: "A possible role for centrosome overduplication in radiation-induced cell death."Oncogene. 19. 5281-5290

[Publications] Honda M.: "Adenovirus-mediated gene transfer of soluble flt-1 receptor inhibits the experimental subretinal neovasucularization."Gene Ther.. 7. 978-985 (2000)

[Publications] Shiose S.: "Gene transfer of a soluble receptor of VEGF inhibits the growth of experimental eyelid malignant melanoma."Invest.Ophthalmol.Vis.Sci.. 41. 2395-2403 (2000)

上野光産業医科大学, 医学部, 教授 (50260378)