1996 Fiscal Year Annual Research Report

新しい作用機序を有する難治性高脂血症治療薬の開発とその応用

Research Project

Project/Area Number	07557073
Research Institution	KYOTO UNIVERSITY
Principal Investigator	北徹京都大学, 医学研究科, 教授 (60161460)
Co-Investigator(Kenkyū-buntansha)	石井賢二京都大学, 医学研究科, 助手 (00212811) 若月芳雄京都大学, 医学研究科, 講師 (40220826) 久米典昭京都大学, 医学研究科, 助手 (20252455) 横出正之京都大学, 医学研究科, 講師 (20252447) 土井俊夫京都大学, 医学研究科, 講師 (60183498)
Keywords	LDL / VLDL / LDL受容体 / アポ蛋白B-100 / MTP / HMG-CoA還元酵素阻害剤 / 家族性複合型高脂血症 / 家族性高コレステロール血症
Research Abstract	ウサギミクロゾームトリグリセリド転送蛋白(MTP)cDNA全長の決定を行なった。その発現ベクターを構築し、MTD蛋白発現をCHO細胞を用いて、確認することに成功した。この過程に予定より時間がかかってしまった。現在以下の実験が進行中である。 1)MTP強制発現モデルの作成 a)培養ウサギ肝細胞へMTP遺伝子を導入してアポ蛋白Bの分泌を解析中である。 b)マウストランスフェリンプロモーターを用いたDNAコンストラクトを構築した。これをマウス胚へ注入し、トランスジェニックマウスの作出を目指している。これは家族性複合型高脂血症モデルとして有用と考えられ、その治療薬の効果判定に有用である。 2)MTP発現抑制モデルの作成 a)MTPcDNAのアンチセンスを作成し、アポ蛋白B-100の分泌抑制効果を検討するため、その作業を進めている。 3)MTP以外にアポ蛋白B-100の翻訳後調節に関与する新たな蛋白の存在をこの研究の過程で見い出した。ウサギ肝細胞抽出物を用いて、抗アポ蛋白B抗体E5Fによる免疫沈降を行ない、アポ蛋白B-100以外にいくつかの蛋白バンドが見い出さた。MTPであり、1つはHSP-70である可能性が高く、その他に未知の蛋白バントが見い出されており、それぞれを解析中である。平成8年度では、MTPcDNAの全長を単離するのに(配列まで正確にするのに)時間がかかり、それを用いた検討を現在行なっているところである。この過程でMTP以外のアポ蛋白B-100の翻訳後調節に関与する蛋白を見い出した。

Research Products
(22 results)

All Other

All Publications (22 results)

[Publications] Tanaka,M.et al.: "Regulation of apolipoprotein B secretion in hepatocytes from Watanabe heritable hyperlipidemic rabbit,ananimal model of familial hyprecholesterolemia." Athelosclerosis. 114. 73-82 (1995)
[Publications] Ochi,H.et al.: "Elevated levels of cyclic AMP inhibits protxein kinase-C independent mechanisms of endothelial PDGF-B chian and TCAM-1 gene induction by lysophosphatidylcholine." Circulation Research. 77. 530-535 (1995)
[Publications] Kita,T et al.: "Lessons concrening human lipoprotein metabolism from the study of the WHHL rabbit." Atherosclerosis. X. 111-113 (1995)
[Publications] Uematsu,M.et al.: "Coexistent myelodysplastic syndrome and non-Hodgkin lymphoma.Report of a case and review of the literature." Int.J.Hematology. 62. 45-51 (1995)
[Publications] Kume,N.et al.: "Involvement of protein kinase C-independent mechanisms in endothelial ICAM-1 up-regulation by lysophosphatidylcholine." Ann.N.Y.Acad.Sci.748. 541-542 (1995)
[Publications] Komatsu,T.et al.: "Lipoprotein glomerulopathy with a new apolipoprotein E phenotype" Am.J.Kidney Diseases. 25. 952-953 (1995)
[Publications] Nishida,R.et al.: "Endoscopic Sclerotherapy in a Rat Model of Esophageal Varices" Scand J.Gastroenterol. 30. 489-496 (1995)
[Publications] Dekigai,H.et al.: "Mechanism of Helicobacterpylori-Associated Gastric Mucosal Injury" Digestive Diseases and Sciences. 40. 1332-1339 (1995)
[Publications] Teramoto,T.et al.: "Clinical Efficacy of fluvastatin for hyperlipidemia in Japanese patients." Am.J.Cardiol.76. 33A-36A (1995)
[Publications] Yokode,M.et al.: "The macrophage and its role in atherogenesis" Internal Medicine. 34. 281-283 (1995)
[Publications] Yokode,M.et al.: "cigarette smoke and lipoprotein modification : a possible interpretation for development of a therosclerosis." Ann.N.Y.Acad.Sci.748. 294-301 (1995)
[Publications] Iehara,N.et al.: "Differentiation of smooth musclephenotypes in mouse masangial cells." Kid.Int.49. 1330-1341 (1996)
[Publications] Iehara,N.et al.: "Advanced glycosylation endoproducts modulate trascriptional regulations of type IV collagen and α-smooth muscle actin on mesangial cells." Nephrology. 118. 141-146 (1996)
[Publications] Uematsu-Yanagita,M.et al.: "Microscopic polyarteritis buring polymyalgis rheumatica remission." Am.J.Kid.Dis.28. 289-291 (1996)
[Publications] Yokode,M.et al.: "Modification of high-and low-density lipoproteins by cigarette smoke oxidants." The Ann.N.Y.Acad.Sci.786. 245-251 (1996)
[Publications] Kita,T.et al.: "Lysophosphatidylcholine induced gene expression of endothelial platelet-derived growth factor-b-chain and intercellular adhesion molecule-1" Medical Science Symposia Series. (in press).
[Publications] Kita,T.et al.: "Induction of endothelial platelrt-derived frowth gactor-b-chain and intercellular adhesion molecule-1 by lysophosphatidylcholine"
[Publications] The Ann.N.Y.Acad.Sci.(in press).
[Publications] Sakai,A.et al.: "P-selectin and vascular cell adhesion molecule-and focally expressed in aortas of hypercholesterolemic rabbits prior to intimal accumulation of Macrophages and T-lymphocytes." Arterioscler Thromb Vasc Biol.(in press).
[Publications] Nishi,E.et al.: "Lysophosphatidylcholine increases expression of heparin-binding epidermal growth factor-like growth factor in human T-lymphocytes."
[Publications] Circulation Research. (in press).
[Publications] Sawamura,T.et al.: "A novel endothelial receptor for oxidized LDL" Nature. (in press).

1996 Fiscal Year Annual Research Report

新しい作用機序を有する難治性高脂血症治療薬の開発とその応用

Principal Investigator

北 徹 京都大学, 医学研究科, 教授 (60161460)

Research Products

[Publications] Tanaka,M.et al.: "Regulation of apolipoprotein B secretion in hepatocytes from Watanabe heritable hyperlipidemic rabbit,ananimal model of familial hyprecholesterolemia." Athelosclerosis. 114. 73-82 (1995)

[Publications] Ochi,H.et al.: "Elevated levels of cyclic AMP inhibits protxein kinase-C independent mechanisms of endothelial PDGF-B chian and TCAM-1 gene induction by lysophosphatidylcholine." Circulation Research. 77. 530-535 (1995)

[Publications] Kita,T et al.: "Lessons concrening human lipoprotein metabolism from the study of the WHHL rabbit." Atherosclerosis. X. 111-113 (1995)

[Publications] Uematsu,M.et al.: "Coexistent myelodysplastic syndrome and non-Hodgkin lymphoma.Report of a case and review of the literature." Int.J.Hematology. 62. 45-51 (1995)

[Publications] Kume,N.et al.: "Involvement of protein kinase C-independent mechanisms in endothelial ICAM-1 up-regulation by lysophosphatidylcholine." Ann.N.Y.Acad.Sci.748. 541-542 (1995)

[Publications] Komatsu,T.et al.: "Lipoprotein glomerulopathy with a new apolipoprotein E phenotype" Am.J.Kidney Diseases. 25. 952-953 (1995)

[Publications] Nishida,R.et al.: "Endoscopic Sclerotherapy in a Rat Model of Esophageal Varices" Scand J.Gastroenterol. 30. 489-496 (1995)

[Publications] Dekigai,H.et al.: "Mechanism of Helicobacterpylori-Associated Gastric Mucosal Injury" Digestive Diseases and Sciences. 40. 1332-1339 (1995)

[Publications] Teramoto,T.et al.: "Clinical Efficacy of fluvastatin for hyperlipidemia in Japanese patients." Am.J.Cardiol.76. 33A-36A (1995)

[Publications] Yokode,M.et al.: "The macrophage and its role in atherogenesis" Internal Medicine. 34. 281-283 (1995)

[Publications] Yokode,M.et al.: "cigarette smoke and lipoprotein modification : a possible interpretation for development of a therosclerosis." Ann.N.Y.Acad.Sci.748. 294-301 (1995)

[Publications] Iehara,N.et al.: "Differentiation of smooth musclephenotypes in mouse masangial cells." Kid.Int.49. 1330-1341 (1996)

[Publications] Iehara,N.et al.: "Advanced glycosylation endoproducts modulate trascriptional regulations of type IV collagen and α-smooth muscle actin on mesangial cells." Nephrology. 118. 141-146 (1996)

[Publications] Uematsu-Yanagita,M.et al.: "Microscopic polyarteritis buring polymyalgis rheumatica remission." Am.J.Kid.Dis.28. 289-291 (1996)

[Publications] Yokode,M.et al.: "Modification of high-and low-density lipoproteins by cigarette smoke oxidants." The Ann.N.Y.Acad.Sci.786. 245-251 (1996)

[Publications] Kita,T.et al.: "Lysophosphatidylcholine induced gene expression of endothelial platelet-derived growth factor-b-chain and intercellular adhesion molecule-1" Medical Science Symposia Series. (in press).

[Publications] Kita,T.et al.: "Induction of endothelial platelrt-derived frowth gactor-b-chain and intercellular adhesion molecule-1 by lysophosphatidylcholine"

[Publications] The Ann.N.Y.Acad.Sci.(in press).

[Publications] Sakai,A.et al.: "P-selectin and vascular cell adhesion molecule-and focally expressed in aortas of hypercholesterolemic rabbits prior to intimal accumulation of Macrophages and T-lymphocytes." Arterioscler Thromb Vasc Biol.(in press).

[Publications] Nishi,E.et al.: "Lysophosphatidylcholine increases expression of heparin-binding epidermal growth factor-like growth factor in human T-lymphocytes."

[Publications] Circulation Research. (in press).

[Publications] Sawamura,T.et al.: "A novel endothelial receptor for oxidized LDL" Nature. (in press).

北徹京都大学, 医学研究科, 教授 (60161460)