Identification and Functional Analysis of Cardiac Specific Singling Molecules and Therapeutic Applications for Cardiovascular Disease

• Project/Area Number: 20390225
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Circulatory organs internal medicine
• Research Institution: Osaka University
• Principal Investigator: TAKASHIMA Seiji Osaka University, 医学系研究科, 独立准教授 (90379272)
• Co-Investigator(Kenkyū-buntansha): MINAMINO Tetsuo 大阪大学, 医学系研究科, 講師 (30379234)
• Co-Investigator(Renkei-kenkyūsha): ASANO Yoshihiro 大阪大学, 医学系研究科, 助教 (60527670) ; TSUKAMOTO Osamu 大阪大学, 医学系研究科, 特任研究員 (80589151) ; KATO Hisakazu 大阪大学, 医学系研究科, 特任研究員 (30589312)
• Research Collaborator: NAKANO Atsushi 大阪大学, 医学系研究科, 特任研究員 ; YAMAZAKI Satoru 国立循環器病研究センター, 室長 (70348796)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥18,850,000 (Direct Cost: ¥14,500,000、Indirect Cost: ¥4,350,000); Fiscal Year 2010: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2009: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2008: ¥9,230,000 (Direct Cost: ¥7,100,000、Indirect Cost: ¥2,130,000)
• Keywords: 組織・細胞 / 生体分子 / 循環器・高血圧 / 細胞・組織

Research Abstract

In this research project, I newly discovered GS protein whose expression is regulated specifically different way in the cardiomyocyte. GS regulates the function of ATP synthesis. We also purified and identified a new AMPK substrate; CLIP-170 and clarified the regulatory role of AMPK in microtubule polymerization. Both discoveries lead to the understanding of novel cellular stress response in cardiomyocyte and the therapeutic approach of the cardiovascular diseases.

Research Products

• [Journal Article] AMPK controls the speed of microtubule polymerization and directional cell migration through CLIP-170 phosphorylation. (2010)
  • Author(s): Nakano A, Kato H, Watanabe T, Min KD, Yamazaki S, Asano Y, Seguchi O, Higo S, Shintani Y, Asanuma H, Asakura M, Minamino T, Kaibuchi K, Mochizuki N, Kitakaze M, Takashima S.
  • Journal Title: Nat Cell Biol. 12(6) Pages: 583-590
  • Peer Reviewed
• [Journal Article] Isoform-specific intermolecular disulfide bond formation of heterochromatin protein 1 (HP1). (2010)
  • Author(s): Higo S, Asano Y, Kato H, Yamazaki S, Nakano A, Tsukamoto O, Seguchi O, Asai M, Asakura M, Asanuma H, Sanada S, Minamino T, Komuro I, Kitakaze M, Takashima S.
  • Journal Title: The Journal of biological chemistry. 285(41) Pages: 31337-31347
  • Peer Reviewed
• [Journal Article] X-box binding protein 1 regulates brain natriuretic peptide through a novel AP1/CRE-like element in cardiomyocytes. (2010)
  • Author(s): Sawada T, Minamino T, Fu HY, Asai M, Okuda K, Isomura T, Yamazaki S, Asano Y, Okada K, Tsukamoto O, Sanada S, Asanuma H, Asakura M, Takashima S, Kitakaze M, Komuro I.
  • Journal Title: Journal of molecular and cellular cardiology. 48(6) Pages: 1280-1289
  • Peer Reviewed
• [Journal Article] Identification of genes related to heart failure using global gene expression profiling of human failing myocardium. (2010)
  • Author(s): Min KD, Asakura M, Liao Y, Nakamaru K, Okazaki H, Takahashi T, Fujimoto K, Ito S, Takahashi A, Asanuma H, Yamazaki S, Minamino T, Sanada S, Seguchi O, Nakano A, Ando Y, Otsuka T, Furukawa H, Isomura T, Takashima S, Mochizuki N, Kitakaze M.
  • Journal Title: Biochem Biophys Res Commun. 393(1) Pages: 55-60
  • Peer Reviewed
• [Journal Article] Antihypertrophic effects of adiponectin on cardiomyocytes are associated with the inhibition of heparin-binding epidermal growth factor signaling. (2010)
  • Author(s): Liao Y, Xuan W, Zhao J, Bin J, Zhao H, Asakura M, Funahashi T, Takashima S, Kitakaze M.
  • Journal Title: Biochem Biophys Res Commun. 393(3) Pages: 519-525
  • Peer Reviewed
• [Journal Article] Anti-human HB-EGF monoclonal antibodies inhibiting ectodomain shedding of HB-EGF and diphtheria toxin binding. (2010)
  • Author(s): Hamaoka M, Chinen I, Murata T, Takashima S, Iwamoto R, Mekada E.
  • Journal Title: Journal of biochemistry. 148(1) Pages: 55-69
  • NAID: 10027877136
  • Peer Reviewed
• [Journal Article] Ablation of C/EBP homologous protein attenuates endoplasmic reticulum-mediated apoptosis and cardiac dysfunction induced by pressure overload. (2010)
  • Author(s): Fu HY, Okada K, Liao Y, Tsukamoto O, Isomura T, Asai M, Sawada T, Okuda K, Asano Y, Sanada S, Asanuma H, Asakura M, Takashima S, Komuro I, Kitakaze M, Minamino T.
  • Journal Title: Circulation. 122(4) Pages: 361-369
  • Peer Reviewed
• [Journal Article] Isoform-specific intermolecular disulfide bond formation of hetero chromatin protein 1 (HP1). (2010)
  • Author(s): Higo, S.Takashima, S., et al.
  • Journal Title: J Biol Chem. Volume: 285 Pages: 31337-47
  • Peer Reviewed
• [Journal Article] AMPK controls the speed of microtubule polymerization and directional cell migration via CLIP-170 phosphorylation. (2010)
  • Author(s): Nakano, A., Takashima, S., et al.
  • Journal Title: Nat.Cell Biol. Volume: 12 Pages: 583-590
  • Peer Reviewed
• [Journal Article] X-box binding protein 1 regulates brain natriuretic peptide through a novel AP1/CRE-like element in cardiomyocytes. (2010)
  • Author(s): Sawada, T., Takashima, S., et al
  • Journal Title: J Mol Cell Cardiol. Volume: 48 Pages: 1280-1289
  • Peer Reviewed
• [Journal Article] Ablation of C/EBP homologous protein attenuates endoplasmic reticulum-mediated apoptosis and cardiac dysfunction induced by pressure overload. (2010)
  • Author(s): Fu, H.Y., Takashima, S., et al
  • Journal Title: Circulation Volume: 122 Pages: 361-9
  • Peer Reviewed
• [Journal Article] Identification of Genes related to Heart Failure Using Global Gene Expression Profiling of Human Failing Myocardium. (2010)
  • Author(s): Min KD, et al.
  • Journal Title: Biochem Biophys Res Commun. 393(1) Pages: 55-60
  • Peer Reviewed
• [Journal Article] FGF8 signaling regulates growth of midbrain dopaminergic axons by inducing semaphorin 3F. (2009)
  • Author(s): Yamauchi K, Mizushima S, Tamada A, Yamamoto N, Takashima S, Murakami F.
  • Journal Title: J Neurosci. 29(13) Pages: 4044-4055
  • Peer Reviewed
• [Journal Article] A single polymorphic amino acid on Toxoplasma gondii kinase ROP16 determines the direct and strain-specific activation of Stat3. (2009)
  • Author(s): Yamamoto M, Standley DM, Takashima S, Saiga H, Okuyama M, Kayama H, Kubo E, Ito H, Takaura M, Matsuda T, Soldati-Favre D, Takeda K.
  • Journal Title: J Exp Med. 206(12) Pages: 2747-2760
  • Peer Reviewed
• [Journal Article] Phosphorylation of myosin regulatory light chain by myosin light chain kinase, and muscle contraction. (2009)
  • Author(s): Takashima S.
  • Journal Title: Circ J. 73(2) Pages: 208-213
  • NAID: 110007042182
  • Peer Reviewed
• [Journal Article] Prolonged targeting of ischemic/reperfused myocardium by liposomal adenosine augments cardioprotection in rats. (2009)
  • Author(s): Takahama H, Minamino T, Asanuma H, Fujita M, Asai T, Wakeno M, Sasaki H, Kikuchi H, Hashimoto K, Oku N, Asakura M, Kim J, Takashima S, Komamura K, Sugimachi M, Mochizuki N, Kitakaze M.
  • Journal Title: J Am Coll Cardiol. 53(8) Pages: 709-717
  • Peer Reviewed
• [Journal Article] Lymphotoxin-alpha3 mediates monocyte-endothelial interaction by TNFR I/NF-kappaB signaling. (2009)
  • Author(s): Suna S, Sakata Y, Shimizu M, Nakatani D, Usami M, Matsumoto S, Mizuno H, Ozaki K, Takashima S, Takeda H, Tanaka T, Hori M, Sato H.
  • Journal Title: Biochem Biophys Res Commun. 379(2) Pages: 374-378
  • Peer Reviewed
• [Journal Article] Methamphetamine directly accelerates beating rate in cardiomyocytes by increasing Ca(2+) entry via L-type Ca(2+) channel. (2009)
  • Author(s): Sugimoto K, Okamura K, Tanaka H, Takashima S, Ochi H, Yamamoto T, Matoba R.
  • Journal Title: Biochem Biophys Res Commun.
  • Peer Reviewed
• [Journal Article] Extracellular protein kinase CK2 is a novel associating protein of neuropilin-1. (2009)
  • Author(s): Shintani Y, Takashima S, Kato H, Komamura K, Kitakaze M.
  • Journal Title: Biochem Biophys Res Commun. 385(4) Pages: 618-623
  • Peer Reviewed
• [Journal Article] Metformin prevents progression of heart failure in dogs: role of AMP-activated protein kinase. (2009)
  • Author(s): Sasaki H, Asanuma H, Fujita M, Takahama H, Wakeno M, Ito S, Ogai A, Asakura M, Kim J, Minamino T, Takashima S, Sanada S, Sugimachi M, Komamura K, Mochizuki N, Kitakaze M.
  • Journal Title: Circulation. 119(19) Pages: 2568-2577
  • Peer Reviewed
• [Journal Article] PKA rapidly enhances proteasome assembly and activity in in vivo canine hearts. (2009)
  • Author(s): Asai M, Tsukamoto O, Minamino T, Asanuma H, Fujita M, Asano Y, Takahama H, Sasaki H, Higo S, Asakura M, Takashima S, Hori M, Kitakaze M.
  • Journal Title: Journal of molecular and cellular cardiology. 46(4) Pages: 452-462
  • Peer Reviewed
• [Journal Article] A single polymorphic amino acid on Toxoplasma gondii kinase ROP16 determines the direct and strain-specific activation of Stat3. (2009)
  • Author(s): Yamamoto M, et al
  • Journal Title: J Exp Med. 206(12) Pages: 2747-60
  • Peer Reviewed
• [Journal Article] Methamphetamine directly accelerates beating rate in cardiomyocytes by increasing Ca(2+) entry via L-type Ca(2+) channel. (2009)
  • Author(s): Sugimoto K, et al.
  • Journal Title: Biochem Biophys Res Commun. 390(4) Pages: 1214-20
  • Peer Reviewed
• [Journal Article] Metformin prevents progression of heart failure in dogs : role of AMP-activated protein kinase. (2009)
  • Author(s): Sasaki H, et al
  • Journal Title: Circulation 119(19) Pages: 2568-77
  • Peer Reviewed
• [Journal Article] PRA rapidly enhances proteasome assembly and activity in in vivo canine hearts (2009)
  • Author(s): Asai M, et al
  • Journal Title: J Mol Cell Cardiol 46(4) Pages: 452-462
  • Peer Reviewed
• [Journal Article] Inhibition of cardiac remodeling by pravastatin is associated with amelioration of endoplasmic reticulum stress. (2008)
  • Author(s): Zhao H, Liao Y, Minamino T, Asano Y, Asakura M, Kim J, Asanuma H, Takashima S, Hori M, Kitakaze M.
  • Journal Title: Hypertens Res. 31(10) Pages: 1977-1987
  • NAID: 10024827861
  • Peer Reviewed
• [Journal Article] Identification of a novel substrate for TNFalpha-induced kinase NUAK2. (2008)
  • Author(s): Yamamoto H, Takashima S, Shintani Y, Yamazaki S, Seguchi O, Nakano A, Higo S, Kato H, Liao Y, Asano Y, Minamino T, Matsumura Y, Takeda H, Kitakaze M.
  • Journal Title: Biochem Biophys Res Commun. 365(3) Pages: 541-547
  • Peer Reviewed
• [Journal Article] Up-regulation of cell adhesion molecule genes in human endothelial cells stimulated by lymphotoxin alpha : DNA microarray analysis. (2008)
  • Author(s): Suna S, Sakata Y, Sato H, Mizuno H, Nakatani D, Shimizu M, Usami M, Takashima S, Takeda H, Hori M.
  • Journal Title: J Atheroscler Thromb. 15(3)
  • NAID: 10022608417
  • Peer Reviewed
• [Journal Article] Atorvastatin slows the progression of cardiac remodeling in mice with pressure overload and inhibits epidermal growth factor receptor activation. (2008)
  • Author(s): Liao Y, Zhao H, Ogai A, Kato H, Asakura M, Kim J, Asanuma H, Minamino T, Takashima S, Kitakaze M.
  • Journal Title: Hypertens Res. 31(2) Pages: 335-344
  • NAID: 10024360118
  • Peer Reviewed
• [Journal Article] Higher mortality in heterozygous neuropilin-1 mice after cardiac pressure overload. (2008)
  • Author(s): Li F, Zhao H, Liao Y, Takashima S, Asano Y, Shintani Y, Hori M, Kitakaze M.
  • Journal Title: Biochem Biophys Res Commun. 370(2) Pages: 317-321
  • Peer Reviewed
• [Journal Article] Identification of p32 as a novel substrate for ATM in heart. (2008)
  • Author(s): Kato H, Takashima S, Asano Y, Shintani Y, Yamazaki S, Seguchi O, Yamamoto H, Nakano A, Higo S, Ogai A, Minamino T, Kitakaze M, Hori M.
  • Journal Title: Biochem Biophys Res Commun. 366(4) Pages: 885-891
  • Peer Reviewed
• [Journal Article] Inhibition of cardiac remodeling by pravastatin is associatedwith ameliorat ion of endoplasmic reticulum stress. (2008)
  • Author(s): Zhao H, et al
  • Journal Title: Hypertens Res. 10 Pages: 1977-1987
  • Peer Reviewed
• [Journal Article] Higher mortality in heterozygous neuropilin-1 mice after cardiac pressure overload. (2008)
  • Author(s): Li F, et al
  • Journal Title: Biochem Biophys Res Commun. 370 Pages: 317-321
  • Peer Reviewed
• [Remarks]
  • URL: http://www.med.osaka-u.ac.jp/jpn/activities/results/2010/002.html
• [Patent(Industrial Property Rights)] 心臓特異的キナーゼの心不全診断および治療への応用 (2009)
  • Inventor(s): 高島成二、瀬口理、朝倉正紀, 北風政史、大塚敏明、中丸健治、合田明日香
  • Industrial Property Rights Holder: 国立循環器病センター総長・第一三共株式会社
  • Filing Date: 2009-10-22
• [Patent(Industrial Property Rights)] 微小管伸長抑制剤をスクリーニングする方法および微小管伸長抑制剤 (2009)
  • Inventor(s): 北風政史、望月直樹、高島成二、中野敦
  • Industrial Property Rights Holder: 財団法人ヒューマンサイエンス振興財団
  • Filing Date: 2009-07-07
• [Patent(Industrial Property Rights)] 心臓特異的キナーゼの心不全診断および治療への応用 (2009)
  • Inventor(s): 高島成二, 瀬口理, 朝倉正紀, 北風政史, 大塚敏明, 中丸健治, 合田明日香
  • Industrial Property Rights Holder: 国立循環器病センター総長・第一三共株式会社
  • Industrial Property Number: 2009-056423
  • Filing Date: 2009-10-22
• [Patent(Industrial Property Rights)] 微小管伸長抑制剤をスクリーニングする方法および微小管伸長抑制剤 (2009)
  • Inventor(s): 北風政史, 望月直樹, 高島成二, 中野敦
  • Industrial Property Rights Holder: 財団法人ヒューマンサイエンス振興財団
  • Industrial Property Number: 2009-160508
  • Filing Date: 2009-07-07