2001 年度実績報告書

心筋の機能発現におけるCD38/サイクリックADPリボース情報伝達系の役割

研究課題

研究課題/領域番号	12470032
研究機関	東北大学
研究代表者	高澤伸東北大学, 大学院・医学系研究科, 助教授 (50187944)
研究分担者	加賀谷豊東北大学, 医学部・付属病院, 助手 (90250779) 那谷耕司東北大学, 大学院・医学系研究科, 助手 (90202233)
キーワード	CD38 / サイクリックADPリボース / ノックアウトマウス / 筋張力 / 細胞内Ca^<2+> / 心筋 / 心肥大
研究概要	病的な心肥大・心不全などの心臓疾患は欧米のみならず、日本における患者数も増加傾向にある。これら本態性心臓疾患の原因は、一部の遺伝子異常によるものを除いて不明な点が多く、その基礎的メカニズムの解明と新しい治療法の開発は、現代医学における最重要課題となっている。本研究では、我々が開発した全身でCD38/サイクリックADPリボース情報伝達系を欠損する「CD38ノックアウトマウス」を用いて、この情報伝達系が心機能・心筋収縮に果たす役割を解明する。平成13年度の研究では以下の成績を得た。 (1)野生型とCD38ノックアウトマウスから心筋(papillary muscle)を分離し、0.5,1,2秒間隔で電気刺激を加え、この際の張力をトランスジューサーで検出した。心筋張力は野生型とCD38ノックアウトマウスで差が認められなかった。 (2)上述の心筋張力測定時に心筋に予めCa^<2+>蛍光剤Fura-2を取り込ませ、340nm/380nmの蛍光強度比から心筋内Ca^<2+>濃度を測定した。電気刺激時の細胞内Ca^<2+>濃度は野生型とCD38ノックアウトマウスで差が認められなかった。以上の結果と前年度に見出したCD38ノックアウトマウスの心肥大を考え合わせると、「CDノックアウト→CD38/サイクリックADPリボース情報伝達系の欠損→心筋機能異常→機能代償変化→心肥大」の可能性が考えられた。心筋機能の代償変化としては細胞内Ca^<2+>濃度上昇が野生型とCD38ノックアウトマウスで差がなかったことから、細胞内Ca^<2+>利用に関連した遺伝子・蛋白質発現変化の可能性が考えられた。

研究成果

(38件)

すべてその他

すべて文献書誌 (38件)

[文献書誌] Fukushi Y: "Identification of cyclic ADP-ribose-dependent mechnisms in pancreatic muscarine Ca^<2+> signaling using CD38 knockout mice"Journal of Biological Chemistry. 276. 649-655 (2001)
[文献書誌] Chini EN: "CD38 is the major enzyme responsible for synthesis of nicotinic acidadenine dinucleptide phosphate in mammalian tissues"Biochemical Journal. 362. 125-130 (2002)
[文献書誌] Antonelli A: "Anti-CD38 autoimmunity in patients with chronic autoimmune thyroiditis or Grave's disease"Clinical & Experimental Immunology. 126. 426-431 (2001)
[文献書誌] Akiyama T: "Activation of Reg gene, a gene for insulin-producing b-cell regeneration : Poly (ADP-ribose) polymerase binds Reg promoter and regulates the transcription by autopoly (ADP-ribosyl) ation"Proc. Natl. Acad. Sci. U.S.A.. 98. 48-53 (2001)
[文献書誌] Yamamoto Y: "Development and prevention of advanced diabetic nephropathy in RAGE-overexpressing mice"Journal of Clinical Investigation. 108. 261-268 (2001)
[文献書誌] Harada K: "Human REG I gene is up-regulated in intrahepatic cholangiocarcinoma and its precursor lesions"Hepatology. 33. 1036-1042 (2001)
[文献書誌] Nakazawa T: "Complete suppression of insulitis and diabetes in NOD mice lacking interferon regulatory factor-1"Journal of Autoimmunity. 17. 119-125 (2001)
[文献書誌] Saito A: "Transgenic CuZn-superoxide dismutase inhibits NO synthase induction in experimental subarachnoid hemorrhage"Stroke. 32. 261-268 (2001)
[文献書誌] Okamoto H: "Activation of cyclin D1 promoter by Reg for β-cell regeneration"Diabetes. (in press). (2002)
[文献書誌] Takasawa S: "Pancreatic β-cell death, regeneration and insulin secretion : Roles of poly (ADP-ribose) polymerase and cyclic ADP-ribose"International Journal of Experimental Diabetes Research. (in press). (2002)
[文献書誌] Okamoto H: "Recent advances in the OKAMOTO model : The CD38-cyclic ADP-ribose signal system and the Reg-Reg receptor system in β-cells"Diabetes. (in press). (2002)
[文献書誌] Unno M: "Production and characterization of Reg konckout mice : Reduced proliferation of pancreatic β-cells in Reg knockout mice"Diabetes. (in press). (2002)
[文献書誌] Miura M: "Effect of transient stretch on intracellular Ca^<2+> during triggered propagated contractions in intact trabeculae"Canadian Journal of Physiological Pharmacology. 79. 68-72 (2001)
[文献書誌] Fukuchi M: "Increased von Wellebrand factor in the endocardium as a local predisposing factor for thrombogenesis in overloaded human atrial appendage"J. Am. Coll. Cardiol. 37. 1436-1442 (2001)
[文献書誌] Takahashi C: "Non selective ET receptor antagonist initiated soon after the onset of myocardial infarction may deteriorate 24-hour survival"J. Cardiovasc. Pharmacol. 38. 29-38 (2001)
[文献書誌] Kon-No Y: "Microvolt T wave alternans in human cardiac hypertrophy : Electrical instability and abnormal myocardial arrangement"J. Cardiovasc. Electrophysiol. 12. 759-763 (2001)
[文献書誌] Nozaki T: "Interaction between sarcomere and mitochondrial length in normoxic and hypoxic rat ventricular papillary muscles"Cardiovasc. Pathol. 10. 125-132 (2001)
[文献書誌] Takeda M: "Gene expression and in situ localization of diacylglycerolkinase isozymes in normal and infarcted rat hearts : Effects of captopril treatment"Circ. Res. 89. 265-272 (2001)
[文献書誌] chida M: "[^<18>F] Labeled diacylglycerol analogue as a potential agent to trace myocardial phosphoinositide metabolism"Nucl. Med. Biol. 28. 815-819 (2001)
[文献書誌] Wakayama Y: "Effects of intracellular Ca^<2+> during triggered propagated contractions"Am. J. Physiol. 281. H2133-H2142 (2001)
[文献書誌] Horiguchi S: "Contribution of Na^+/Ca^<2+> exchanger on the regulation of myogenic tone in isolated rat small arteries"Acta Physiol. Scand. 173. 167-173 (2001)
[文献書誌] Watanabe J: "Declining trend in the in-hospital case-fatality rate from acute myocardial infarction in Miyagi Prefecture from 1980 to 1999"Jpn. Circ. J.. 65. 941-946 (2001)
[文献書誌] Kaneta T: "Imaging of ischemic viable myocardium using a new [^<18>F] labeled 2-nitroimidazole analog, [1^8F] FRP170 : Comparison with myocardial perfusion, fatty acid metabolism and glucose metabolism"J. Nucl. Med.. 43. 109-116 (2001)
[文献書誌] Okamoto H: "Enhancement of Reg-induced β-cell regeneration by hepatocyte growth factor"Diabetes. 50・suppl.2. A336-A336 (2001)
[文献書誌] 那谷耕司: "Reg遺伝子の過剰発現によるNODマウスの糖尿病発症抑制"糖尿病. 44・Suppl.1. S90-S90 (2001)
[文献書誌] 中川圭: "Regによる膵β細胞massの調節におけるHGFの役割"糖尿病. 44・Suppl.1. S90-S90 (2001)
[文献書誌] 米倉秀人: "糖化蛋白受容体(receptor for AGE,RAGE)の分子多様性とAGE結合能"糖尿病. 44・Suppl.1. S191-S191 (2001)
[文献書誌] 小林誠一: "インスリン産生細胞増殖因子Reg受容体の構造・発現・機能"生化学. 73・2. 132-132 (2001)
[文献書誌] 秋山貴子: "Reg遺伝子の転写誘導とポリADPチボシル化による転写調節機構"生化学. 73・2. 132-132 (2001)
[文献書誌] 那谷耕司: "膵β細胞でReg遺伝子を過剰発現するNODマウスでは糖尿病発症が抑制される"生化学. 73・8. 1012-1012 (2001)
[文献書誌] 中川圭: "膵β細胞におけるHGF遺伝子の転写誘導とその意義"生化学. 73・8. 1011-1011 (2001)
[文献書誌] 米倉秀人: "後期糖化反応生成物受容体(receptor for AGE, RAGE)の分子多様性の発見"生化学. 73・8. 1021-1021 (2001)
[文献書誌] Petrova RG: "AGE-Induced Impairment of Calcium Transient in Cardiac Myocytes"生化学. 73・2. 1022-1022 (2001)
[文献書誌] 高沢伸: "Reg-Reg受容体によるβ細胞cyclin D1遺伝子の活性化"糖尿病. 45(in press). (2002)
[文献書誌] 中川圭: "インスリン産生細胞におけるHGF遺伝子の誘導とその意義"生化学. 74(in press). (2002)
[文献書誌] Okamoto H: "Encyclopedia of Molecular Medicine"John Wiley & Sons, Inc.. 4 (2002)
[文献書誌] Takasawa S: "Cyclic ADP-ribose and NAADP : Structure, Metabolism and Physiological Functions"Kluwer (in press). (2002)
[文献書誌] 海野倫明: "分子糖尿病学の進歩-基礎から臨床まで-"渥美義仁, 門脇孝, 春日雅人, 清野進(金原出版). 5 (2001)

2001 年度 実績報告書

心筋の機能発現におけるCD38/サイクリックADPリボース情報伝達系の役割

研究代表者

高澤 伸 東北大学, 大学院・医学系研究科, 助教授 (50187944)

研究成果

[文献書誌] Fukushi Y: "Identification of cyclic ADP-ribose-dependent mechnisms in pancreatic muscarine Ca^<2+> signaling using CD38 knockout mice"Journal of Biological Chemistry. 276. 649-655 (2001)

[文献書誌] Chini EN: "CD38 is the major enzyme responsible for synthesis of nicotinic acidadenine dinucleptide phosphate in mammalian tissues"Biochemical Journal. 362. 125-130 (2002)

[文献書誌] Antonelli A: "Anti-CD38 autoimmunity in patients with chronic autoimmune thyroiditis or Grave's disease"Clinical & Experimental Immunology. 126. 426-431 (2001)

[文献書誌] Akiyama T: "Activation of Reg gene, a gene for insulin-producing b-cell regeneration : Poly (ADP-ribose) polymerase binds Reg promoter and regulates the transcription by autopoly (ADP-ribosyl) ation"Proc. Natl. Acad. Sci. U.S.A.. 98. 48-53 (2001)

[文献書誌] Yamamoto Y: "Development and prevention of advanced diabetic nephropathy in RAGE-overexpressing mice"Journal of Clinical Investigation. 108. 261-268 (2001)

[文献書誌] Harada K: "Human REG I gene is up-regulated in intrahepatic cholangiocarcinoma and its precursor lesions"Hepatology. 33. 1036-1042 (2001)

[文献書誌] Nakazawa T: "Complete suppression of insulitis and diabetes in NOD mice lacking interferon regulatory factor-1"Journal of Autoimmunity. 17. 119-125 (2001)

[文献書誌] Saito A: "Transgenic CuZn-superoxide dismutase inhibits NO synthase induction in experimental subarachnoid hemorrhage"Stroke. 32. 261-268 (2001)

[文献書誌] Okamoto H: "Activation of cyclin D1 promoter by Reg for β-cell regeneration"Diabetes. (in press). (2002)

[文献書誌] Takasawa S: "Pancreatic β-cell death, regeneration and insulin secretion : Roles of poly (ADP-ribose) polymerase and cyclic ADP-ribose"International Journal of Experimental Diabetes Research. (in press). (2002)

[文献書誌] Okamoto H: "Recent advances in the OKAMOTO model : The CD38-cyclic ADP-ribose signal system and the Reg-Reg receptor system in β-cells"Diabetes. (in press). (2002)

[文献書誌] Unno M: "Production and characterization of Reg konckout mice : Reduced proliferation of pancreatic β-cells in Reg knockout mice"Diabetes. (in press). (2002)

[文献書誌] Miura M: "Effect of transient stretch on intracellular Ca^<2+> during triggered propagated contractions in intact trabeculae"Canadian Journal of Physiological Pharmacology. 79. 68-72 (2001)

[文献書誌] Fukuchi M: "Increased von Wellebrand factor in the endocardium as a local predisposing factor for thrombogenesis in overloaded human atrial appendage"J. Am. Coll. Cardiol. 37. 1436-1442 (2001)

[文献書誌] Takahashi C: "Non selective ET receptor antagonist initiated soon after the onset of myocardial infarction may deteriorate 24-hour survival"J. Cardiovasc. Pharmacol. 38. 29-38 (2001)

[文献書誌] Kon-No Y: "Microvolt T wave alternans in human cardiac hypertrophy : Electrical instability and abnormal myocardial arrangement"J. Cardiovasc. Electrophysiol. 12. 759-763 (2001)

[文献書誌] Nozaki T: "Interaction between sarcomere and mitochondrial length in normoxic and hypoxic rat ventricular papillary muscles"Cardiovasc. Pathol. 10. 125-132 (2001)

[文献書誌] Takeda M: "Gene expression and in situ localization of diacylglycerolkinase isozymes in normal and infarcted rat hearts : Effects of captopril treatment"Circ. Res. 89. 265-272 (2001)

[文献書誌] chida M: "[^<18>F] Labeled diacylglycerol analogue as a potential agent to trace myocardial phosphoinositide metabolism"Nucl. Med. Biol. 28. 815-819 (2001)

[文献書誌] Wakayama Y: "Effects of intracellular Ca^<2+> during triggered propagated contractions"Am. J. Physiol. 281. H2133-H2142 (2001)

[文献書誌] Horiguchi S: "Contribution of Na^+/Ca^<2+> exchanger on the regulation of myogenic tone in isolated rat small arteries"Acta Physiol. Scand. 173. 167-173 (2001)

[文献書誌] Watanabe J: "Declining trend in the in-hospital case-fatality rate from acute myocardial infarction in Miyagi Prefecture from 1980 to 1999"Jpn. Circ. J.. 65. 941-946 (2001)

[文献書誌] Kaneta T: "Imaging of ischemic viable myocardium using a new [^<18>F] labeled 2-nitroimidazole analog, [1^8F] FRP170 : Comparison with myocardial perfusion, fatty acid metabolism and glucose metabolism"J. Nucl. Med.. 43. 109-116 (2001)

[文献書誌] Okamoto H: "Enhancement of Reg-induced β-cell regeneration by hepatocyte growth factor"Diabetes. 50・suppl.2. A336-A336 (2001)

[文献書誌] 那谷耕司: "Reg遺伝子の過剰発現によるNODマウスの糖尿病発症抑制"糖尿病. 44・Suppl.1. S90-S90 (2001)

[文献書誌] 中川 圭: "Regによる膵β細胞massの調節におけるHGFの役割"糖尿病. 44・Suppl.1. S90-S90 (2001)

[文献書誌] 米倉秀人: "糖化蛋白受容体(receptor for AGE,RAGE)の分子多様性とAGE結合能"糖尿病. 44・Suppl.1. S191-S191 (2001)

[文献書誌] 小林誠一: "インスリン産生細胞増殖因子Reg受容体の構造・発現・機能"生化学. 73・2. 132-132 (2001)

[文献書誌] 秋山貴子: "Reg遺伝子の転写誘導とポリADPチボシル化による転写調節機構"生化学. 73・2. 132-132 (2001)

[文献書誌] 那谷耕司: "膵β細胞でReg遺伝子を過剰発現するNODマウスでは糖尿病発症が抑制される"生化学. 73・8. 1012-1012 (2001)

[文献書誌] 中川 圭: "膵β細胞におけるHGF遺伝子の転写誘導とその意義"生化学. 73・8. 1011-1011 (2001)

[文献書誌] 米倉秀人: "後期糖化反応生成物受容体(receptor for AGE, RAGE)の分子多様性の発見"生化学. 73・8. 1021-1021 (2001)

[文献書誌] Petrova RG: "AGE-Induced Impairment of Calcium Transient in Cardiac Myocytes"生化学. 73・2. 1022-1022 (2001)

[文献書誌] 高沢 伸: "Reg-Reg受容体によるβ細胞cyclin D1遺伝子の活性化"糖尿病. 45(in press). (2002)

[文献書誌] 中川 圭: "インスリン産生細胞におけるHGF遺伝子の誘導とその意義"生化学. 74(in press). (2002)

[文献書誌] Okamoto H: "Encyclopedia of Molecular Medicine"John Wiley & Sons, Inc.. 4 (2002)

[文献書誌] Takasawa S: "Cyclic ADP-ribose and NAADP : Structure, Metabolism and Physiological Functions"Kluwer (in press). (2002)

[文献書誌] 海野倫明: "分子糖尿病学の進歩-基礎から臨床まで-"渥美義仁, 門脇 孝, 春日雅人, 清野 進(金原出版). 5 (2001)

2001 年度実績報告書

高澤伸東北大学, 大学院・医学系研究科, 助教授 (50187944)

[文献書誌] 中川圭: "Regによる膵β細胞massの調節におけるHGFの役割"糖尿病. 44・Suppl.1. S90-S90 (2001)

[文献書誌] 中川圭: "膵β細胞におけるHGF遺伝子の転写誘導とその意義"生化学. 73・8. 1011-1011 (2001)

[文献書誌] 高沢伸: "Reg-Reg受容体によるβ細胞cyclin D1遺伝子の活性化"糖尿病. 45(in press). (2002)

[文献書誌] 中川圭: "インスリン産生細胞におけるHGF遺伝子の誘導とその意義"生化学. 74(in press). (2002)

[文献書誌] 海野倫明: "分子糖尿病学の進歩-基礎から臨床まで-"渥美義仁, 門脇孝, 春日雅人, 清野進(金原出版). 5 (2001)