1996 Fiscal Year Annual Research Report

心筋細胞の文化異常と病態形式

Research Project

Project/Area Number	06274105
Research Institution	Kurume University
Principal Investigator	古賀義則久留米大学, 医学部, 教授 (50080669)
Co-Investigator(Kenkyū-buntansha)	古川哲史東京医科歯科大学, 難治疾患研究所, 助手 (80251552) 松原弘明関西医科大学, 講師 (10239072) 永井良三群馬大学, 医学部, 教授 (60207975) 杉浦清了東京大学, 医学部, 助手 (10272551) 堀久枝東京医科歯科大学, 難治疾患研究所, 助手 (80014190)
Keywords	肥大型心筋症 / QT延長症候群 / ミトコンドリア心筋症 / サルコメア蛋白遺伝子異常 / K^+チャンネル遺伝子 / Cl^-チャンネル遺伝子 / HERG遺伝子 / インビトロ運動再構築系
Research Abstract	本研究の目的は心筋に特異的に分化した機能蛋白の異常を分析し、その分子機構の解明を行うことである。肥大型心筋症ついては木村、堀はこれまでに報告された心筋βミオシン重鎖、トロポニンT、αトロポミオシン、ミオシン結合蛋白C以外に新たにミオシンアルカリ軽鎖、調節軽鎖、トロポニンlの遺伝子変異を見出し、また本邦に多い心尖部肥大型の一部にもサルコメア異変を発見した。古賀は遺伝子型と臨床病型の関係を検討し、ミオシン重鎖変異例は典型的臨床像を示すのに対してトロポニンT変異例は収縮不全を伴う重症例が多く、ミオシン結合蛋白C変異例は心筋病変が軽症であることを示した。杉浦はインビトロ運動再構成系を用いて遺伝子工学的に作製した変異ミオシンが収縮機能を障害し、本症の予後を規定する可能性を示した。QT延長症候群については長井はKVLQTlおよびHERG遺伝子で10種類の異変を同定し、このうち9種は日本人で新たに発見された。また変異HERGはK^+チャンネルを抑制しdominant negative機構により本症を発症させていることを示した。心筋電解質移送蛋白については松原は遅延整流型K^+チャンネルであるKv1.5をクローニングし、cAMPがその転写を増加させること、肥大心ではKv1.5の発現低下が活動電位延長に関与することを示した。古川は心筋伸展刺激活性化Cl^-チャンネルの単離・構造決定を行ない、アミノ端が伸展刺激応答に重要な部位であることを示した。ミトコンドリア心筋症については蛋白合成に関わるtRNA,rRNA遺伝子異常が予後不良なことを明らかにした。以上の様に本研究では臨床的には肥大型心筋症、QT延長症候群、ミトコンドリア心筋症の遺伝子異常を解明した。さらに分子生物学的にK^+、Cl^-チャンネル遺伝子のクローニングを行い、心筋細胞の分化異常と病態形式のメカニズムを明らかにし、これらの疾患の治療法の確立の糸口をつかむことができた。

Research Products
(19 results)

All Other

All Publications (19 results)

[Publications] 古賀義則他: "肥大型心筋症の遺伝子異常と病態・治療" 循環器専門医. 4. 5-14 (1996)
[Publications] Koyanagi T,et al: "DNA typing of HLA class II genes in Japanese patients with rheumatic heart disease" J Mol Cell Cardiol. 28. 1349-1353 (1996)
[Publications] Koga Y,et al: "Clinical manifestations of hypertrophic cardiomyopathy with mutations in the cardiac heta-myosin heavy chain gene or cardiac troponin T gene" J Cardiac Failure. 2. S97-S103 (1996)
[Publications] Yamada H,et al: "Dystroglycan is a dual receptor for agrin and laminin-2 in Schwann cell membrane" J Biol Chem. 271. 23418-23423 (1996)
[Publications] Kitaoka M,et al: "Differential expressions of collagen type IV,III and I during the development of invasive tropoblasts in rats" Developmental Dynamics. 207. 319-331 (1996)
[Publications] Mizuta T,et al: "Characterization of monoclonal antibodies recognizing human merosin and their use in affinity purification of native" Hybrydoma. 15. 373-378 (1996)
[Publications] Sata M,et al: "Coupling between myosin ATPase cycle and creatinin kinase cycle facilitates cardiac actomyosin sliding in vitro : A clue to mechanical dysfunction during myocardial ischemia" Circulation. 93. 310-317 (1996)
[Publications] Sugiura S,et al: "Different cardiac myosin isoform exhibit equal force-generating ability in vitro" Biochim Biophys Acta. 1273. 73-76 (1996)
[Publications] Fujita S,et al: "Characterization of mutant myosins of Dictiostelium Discoideum equivalent to human hypertrophic cardiomyopathy mutants" J Clin Invest. (in press). (1997)
[Publications] Arai M,et al: "Sarcoplasmic reticulum genes are upregulated in mild cardiac hypertrophy but downregulated in severe cardiac hypertrophy induced by pressure overload" J Mol Cell Cardiol. 28. 1583-1590 (1996)
[Publications] Watanabe,M et al: "Structure and characterization of the 5'-flanking region of the mouse smooth muscle myosin heavy chain (SM1/2) gene" Circ Res. 78. 978-989 (1996)
[Publications] Suzaki,T et al: "Preferential differentiation of P19 mouse embryonal carcinoma cells into smooth muscle cells ; Use of retinoic acid and antisense against the central nervous system-specific POU transcription factor Brn-2" Circ Res. 78. 395-404 (1996)
[Publications] Sawada Y,et al: "Co-elevation of brain natriuretic peptide and proprotein-processing endoprotease fuin after myocardial infarction in rats" FEBS Letters. 400. 177-182 (1997)
[Publications] Tanaka T,et al: "Four novel KVLQl and four novel HERG mutations in familial long QT syndrome" Circulation. 95. 565-567 (1997)
[Publications] Mori Y,et al: "Gll3 cell-specific expression of Kv 1.5 gene,Regulation by a silencer containing dinucleotide repititive element" J Biol Chem. 270. 27788-27796 (1995)
[Publications] Furukawa T,et al: "Functional linkage of the cardiac ATP-sensitive K^+ channel to the actin cytoskeleton" Pflugers Archives. 431. 504-512 (1996)
[Publications] 中島忠他: "QT延長症候群の原因遺伝子とその機能" 呼吸と循環. 45. 121-128 (1997)
[Publications] Hayakawa M,et al: "Age-related extensive fragmentation of mitochondrial DNA into minicircles" Biochem Biophys Res Commun. 226. 369-377 (1996)
[Publications] Sugiyama S,et al: "Effects of ubiquinone enriched diet on deterioration of mitochondrial respiratory function caused by fried beef derived mutagenic factors in rats" Biochem Mol Biol Int. 40. 305-314 (1996)

1996 Fiscal Year Annual Research Report

心筋細胞の文化異常と病態形式

Principal Investigator

古賀 義則 久留米大学, 医学部, 教授 (50080669)

Research Products

[Publications] 古賀義則他: "肥大型心筋症の遺伝子異常と病態・治療" 循環器専門医. 4. 5-14 (1996)

[Publications] Koyanagi T,et al: "DNA typing of HLA class II genes in Japanese patients with rheumatic heart disease" J Mol Cell Cardiol. 28. 1349-1353 (1996)

[Publications] Koga Y,et al: "Clinical manifestations of hypertrophic cardiomyopathy with mutations in the cardiac heta-myosin heavy chain gene or cardiac troponin T gene" J Cardiac Failure. 2. S97-S103 (1996)

[Publications] Yamada H,et al: "Dystroglycan is a dual receptor for agrin and laminin-2 in Schwann cell membrane" J Biol Chem. 271. 23418-23423 (1996)

[Publications] Kitaoka M,et al: "Differential expressions of collagen type IV,III and I during the development of invasive tropoblasts in rats" Developmental Dynamics. 207. 319-331 (1996)

[Publications] Mizuta T,et al: "Characterization of monoclonal antibodies recognizing human merosin and their use in affinity purification of native" Hybrydoma. 15. 373-378 (1996)

[Publications] Sata M,et al: "Coupling between myosin ATPase cycle and creatinin kinase cycle facilitates cardiac actomyosin sliding in vitro : A clue to mechanical dysfunction during myocardial ischemia" Circulation. 93. 310-317 (1996)

[Publications] Sugiura S,et al: "Different cardiac myosin isoform exhibit equal force-generating ability in vitro" Biochim Biophys Acta. 1273. 73-76 (1996)

[Publications] Fujita S,et al: "Characterization of mutant myosins of Dictiostelium Discoideum equivalent to human hypertrophic cardiomyopathy mutants" J Clin Invest. (in press). (1997)

[Publications] Arai M,et al: "Sarcoplasmic reticulum genes are upregulated in mild cardiac hypertrophy but downregulated in severe cardiac hypertrophy induced by pressure overload" J Mol Cell Cardiol. 28. 1583-1590 (1996)

[Publications] Watanabe,M et al: "Structure and characterization of the 5'-flanking region of the mouse smooth muscle myosin heavy chain (SM1/2) gene" Circ Res. 78. 978-989 (1996)

[Publications] Suzaki,T et al: "Preferential differentiation of P19 mouse embryonal carcinoma cells into smooth muscle cells ; Use of retinoic acid and antisense against the central nervous system-specific POU transcription factor Brn-2" Circ Res. 78. 395-404 (1996)

[Publications] Sawada Y,et al: "Co-elevation of brain natriuretic peptide and proprotein-processing endoprotease fuin after myocardial infarction in rats" FEBS Letters. 400. 177-182 (1997)

[Publications] Tanaka T,et al: "Four novel KVLQl and four novel HERG mutations in familial long QT syndrome" Circulation. 95. 565-567 (1997)

[Publications] Mori Y,et al: "Gll3 cell-specific expression of Kv 1.5 gene,Regulation by a silencer containing dinucleotide repititive element" J Biol Chem. 270. 27788-27796 (1995)

[Publications] Furukawa T,et al: "Functional linkage of the cardiac ATP-sensitive K^+ channel to the actin cytoskeleton" Pflugers Archives. 431. 504-512 (1996)

[Publications] 中島忠 他: "QT延長症候群の原因遺伝子とその機能" 呼吸と循環. 45. 121-128 (1997)

[Publications] Hayakawa M,et al: "Age-related extensive fragmentation of mitochondrial DNA into minicircles" Biochem Biophys Res Commun. 226. 369-377 (1996)

[Publications] Sugiyama S,et al: "Effects of ubiquinone enriched diet on deterioration of mitochondrial respiratory function caused by fried beef derived mutagenic factors in rats" Biochem Mol Biol Int. 40. 305-314 (1996)

古賀義則久留米大学, 医学部, 教授 (50080669)

[Publications] 中島忠他: "QT延長症候群の原因遺伝子とその機能" 呼吸と循環. 45. 121-128 (1997)