• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to previous page

Study of a novel network regulating calcium homeostasis

Research Project

Project/Area Number 14207007
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Pathological medical chemistry
Research InstitutionKyoto University

Principal Investigator

NABESHIMA Yo-ichi  Kyoto University, Graduate School of Medicine, Professor, 医学研究科, 教授 (60108024)

Co-Investigator(Kenkyū-buntansha) FUJIMORI Toshihiko  Kyoto University, Graduate School of Medicine, Assistant Professor, 医学研究科, 助手 (80301274)
Project Period (FY) 2002 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥50,050,000 (Direct Cost: ¥38,500,000、Indirect Cost: ¥11,550,000)
Fiscal Year 2004: ¥9,750,000 (Direct Cost: ¥7,500,000、Indirect Cost: ¥2,250,000)
Fiscal Year 2003: ¥19,500,000 (Direct Cost: ¥15,000,000、Indirect Cost: ¥4,500,000)
Fiscal Year 2002: ¥20,800,000 (Direct Cost: ¥16,000,000、Indirect Cost: ¥4,800,000)
KeywordsKlotho / NaK-ATPase / 1α-hydroxylase / Aging / Calcium / Vitamin D / 個体老化 / Klotho遺伝子 / カルシウムホメオスタシス / 1-α hydroxylase / グルクロニダーゼ / 1-αhydroxylase
Research Abstract

We recently developed a unique short lifespan mouse strain in which a single gene mutation caused multiple aging-related disorders and identified the responsible gene as klotho. The klotho gene is expressed principally in the important tissues for calcium homeostasis such as distal tubule cells of the kidney, choroid plexus, and theparathyroid gland. The most representative phenotypes in kl-/-mice seem to be caused by abnormalities in calcium metabolism.
To study the molecular function and the biological role of the Klotho protein, we tried to isolate Klotho binding proteins and identified Na+/K+ ATPase. Klotho is critical for the regulation of recruitment of Na+/K+ ATPase to cell surface membrane in response to the extra-cellular conditions. We next confirmed that Na+/K+ ATPase activity correlates with the amounts of Na+/K+ATPase present on the cell surface. Therefore, Klotho is involved in the regulation of Na+/K+ ATPase activity by mediating the extra-cellular signal to up or down regulation of the recruitment of Na+/K+ ATPase to cell surface.
As Na+/K+ATPase has been reported to be a fundamental regulator of multiple phenomena, Klotho can be involved in the regulation of multiple biological events by modulating the action of Na+/K+ATPase and thus deficiency of Klotho leads to multiple phenotypes.

Report

(4 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • 2002 Annual Research Report
  • Research Products

    (59 results)

All 2004 2003 2002 Other

All Journal Article (41 results) Patent(Industrial Property Rights) (2 results) Publications (16 results)

  • [Journal Article] Klotho is a novel β-glucuronidase capable of hydrolyzing steroid β-glucuronides.2004

    • Author(s)
      Tohyama O., et al.
    • Journal Title

      J.Biol.Chem. 279(11)

      Pages: 9777-9784

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Sinoatrial Node Dysfunction and Early Unexpected Death of Mice with a Defect of Klotho Gene Expression.2004

    • Author(s)
      K Takeshita et al.
    • Journal Title

      Circulation 109(14)

      Pages: 1776-1782

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Secreted Klotho protein in sera and CSF : Implication for post-translational cleavage in release of Klotho protein from cell membrane.2004

    • Author(s)
      Imura A.et al.
    • Journal Title

      FEBS Letter 565(1-3)

      Pages: 143-147

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Angiogenesis and vasculogenesis are impaired in the precocious-aging Klotho mouse.2004

    • Author(s)
      Shimada T.et al.
    • Journal Title

      Circulation 110

      Pages: 1148-1155

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Klotho deficient mouse : an in vivo model for human aging.2004

    • Author(s)
      Nabeshima Y.et al.
    • Journal Title

      Drug Discovery Today : Disease Models 1(3)

      Pages: 223-227

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Klotho is a novel β-glucuronidase capable of hydrolyzing steroid β-glucuronides.2004

    • Author(s)
      Tohyama O.
    • Journal Title

      J.Biol Chem. 279(11)

      Pages: 9777-9784

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Sinoatrial Node Dysfunction and Early Unexpected Death of Mice with a Defect of Klotho Gene Expression.2004

    • Author(s)
      Takeshita, K.
    • Journal Title

      Circulation 109(14)

      Pages: 1776-1782

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Secreted Klotho protein in sera and CSF : Implication for post-translational cleavage in release ofKlotho protein from cell membrane.2004

    • Author(s)
      Imura A.
    • Journal Title

      FEBS Letter 565(1-3)

      Pages: 143-147

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Angiogenesis and vasculogenesis are impaired in the precocious-aging Klotho mouse.2004

    • Author(s)
      Shimada T.
    • Journal Title

      Circulation 110

      Pages: 1148-1155

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Models Klotho deficient mouse : an in vivo model for human aging.2004

    • Author(s)
      Nabeshima Y.
    • Journal Title

      Drug Discovery Today : Disease Vol.1(3)

      Pages: 223-227

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Sinoatrial Node Dysfunction and Early Unexpected Death of Mice with a Defect of Klotho Gene Expression.2004

    • Author(s)
      K Takeshia et al.
    • Journal Title

      Circulation 109(14)

      Pages: 1776-1782

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Secreted Klotho protein in sera and CSF : Implication for post-translational cleavage in release of Klotho protein from cell membrane.2004

    • Author(s)
      Imura A. et al.
    • Journal Title

      FEBS Letter 565(1-3)

      Pages: 143-147

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Angiogenesis and vasculogenesis are impaired in the precocious-aging Klotho mouse.2004

    • Author(s)
      Shimada T. et al.
    • Journal Title

      Circulation 110

      Pages: 1148-1155

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Klotho deficient mouse : an in vivo model for human aging.2004

    • Author(s)
      Nabeshima Y. et al.
    • Journal Title

      Drug Discovery Today : Disease Models 1(3)

      Pages: 223-227

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Cognition impairment in the genetic model of aging, klotho gene mutant mice : A role of oxidative stress.2003

    • Author(s)
      Nagai T., et al.
    • Journal Title

      Faseb J. 17(1)

      Pages: 50-52

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Upregulation of cAMP is a new functional signal pathway of Klotho in endotherial cells.2003

    • Author(s)
      Yang J.et al.
    • Journal Title

      Biochem.Biophys.Res.Comm. 301(2)

      Pages: 424-429

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Regulation of stanniocalcin 1 and 2 expression in the kidney by klotho gene.2003

    • Author(s)
      Yahata K.et al.
    • Journal Title

      Biochem.Biophys.Res.Commun. 310(1)

      Pages: 128-134

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Klotho, a gene related to a syndrome resembling human premature aging, functions in a negative regulatory circuit of vitamin D endocrine system.2003

    • Author(s)
      Tsujikaw H.et al.
    • Journal Title

      Molecular Endcrinology 17(12)

      Pages: 2393-2403

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Cognition impairment in the genetic model of aging, klotho gene mutant mice : A role of oxidative stress.2003

    • Author(s)
      Nagai T.
    • Journal Title

      Faseb J. 17(1)

      Pages: 50-52

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Upregulation of cAMP is a new functional signal pathway of Klotho in endotherial cells.2003

    • Author(s)
      Yang J.
    • Journal Title

      Biochem.Biophys.Res.Comm.

      Pages: 424-429

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Oct Regulation of stanniocalcin 1 and 2 expression in the kidney by klotho gene.2003

    • Author(s)
      Yahata K
    • Journal Title

      Biochem Biophys Res Commun. 310(1)

      Pages: 128-134

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Klotho, a gene related to a syndrome resembling human premature aging, functions in a negative regulatory circuit of vitamin D endocrine system.2003

    • Author(s)
      Tsujikaw H.
    • Journal Title

      Molecular Endcrinology 17(12)

      Pages: 2393-2403

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Mediation of unusually high concentrations of 1,25-dihydroxyvitamin D3 in homozygous klotho mutant mice by increased expression of renal 1 alpha-hydroxylase gene.2002

    • Author(s)
      Yoshida T.et al.
    • Journal Title

      Endocrinology 143

      Pages: 683-689

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Identification of a novel mouse membrane-bound family 1 glycosidase-like protein, which carries an atypical active site structure.2002

    • Author(s)
      Ito S.et al.
    • Journal Title

      Biochem.Biophys.Acta 1576(3)

      Pages: 341-345

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Defects in growth and bone metabolism in klotho mutant mice are resistant to growth hormone treatment.2002

    • Author(s)
      Kashimada K.et al.
    • Journal Title

      J.Endcrinology 174(3)

      Pages: 403-410

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Klotho protein deficiency leads to overactivation of (Mu)-calpain2002

    • Author(s)
      Manya H.et al.
    • Journal Title

      J.Biol.Chem. 277(38)

      Pages: 35503-35508

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Klotho gene polymorphisms associated with bone density of aged postmenopausal women.2002

    • Author(s)
      Kawano K.et al.
    • Journal Title

      J.Bone and Mineral Res 17(10)

      Pages: 1744-1751

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Double mutations in klotho and osteoprotegerin gene loci rescued osteopetrotic phenotype.2002

    • Author(s)
      Yamashita T.et al.
    • Journal Title

      Endocrinology. 143(12)

      Pages: 4711-4717

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Increased expression of plasminogen activator inhibitor-1 with fibrin deposition in a murine model of aging, Klotho mouse.2002

    • Author(s)
      Takeshita K.et al.
    • Journal Title

      Semin Thromb Hemost. 28(6)

      Pages: 545-553

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Klotho : A fundamental regulator of aging.2002

    • Author(s)
      Nabeshima Y.
    • Journal Title

      Ageing Res.Rev. 1(4)

      Pages: 627-638

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Mediation of unusually high concentrations of 1,25-dihydroxyvitamin D3 in homozygous klotho mutant mice by increased expression of renal 1 alpha-hydroxylase gene.2002

    • Author(s)
      Yoshida T.
    • Journal Title

      Endocrinology 143

      Pages: 683-689

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Identification of a novel mouse membrane-bound family 1 glycosidase-like protein, which carries an atypical active site structure.2002

    • Author(s)
      Ito S.
    • Journal Title

      Biochem.Biophys.Acta 1576(3)

      Pages: 341-345

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Klotho protein deficiency leads to overactivation of (Mu)-calpain2002

    • Author(s)
      Manya H.
    • Journal Title

      J.Biol.Chem. 277(38)

      Pages: 35503-35508

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Klotho gene polymorphisms associated with bone density of aged postmenopausal women.2002

    • Author(s)
      Kawano K.
    • Journal Title

      J.Bone and Mineral Res. 17(10)

      Pages: 1744-1751

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Increased expression of plasminogen activator inhibitor-1 with fibrin deposition in a murine model of aging, Klotho mouse.2002

    • Author(s)
      Takeshita K.
    • Journal Title

      Semin Thromb Hemost.Dec 28(6)

      Pages: 545-553

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Klotho : A fundamental regulator of aging.2002

    • Author(s)
      Nabeshima Y.
    • Journal Title

      Ageing Res.Rev. 1

      Pages: 627-638

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Impaired negative feedback suppression of bile acid synthesis in mice lacking βKlotho.

    • Author(s)
      Ito S.et al.
    • Journal Title

      J.Clin.Invest. (in press)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] in growth and bone metabolism in klotho mutant mice are resistant to growth hormone treatment.

    • Author(s)
      Kashimada K.
    • Journal Title

      Endcrinology 2002 Sep 174(3)

      Pages: 403-410

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Double mutations in klotho and osteoprotegerin gene loci rescued osteopetrotic phenotype.

    • Author(s)
      Yamashita T.
    • Journal Title

      Endocrinology 2002 Dec 143(12)

      Pages: 4711-4717

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] The in vivo roles of STEF/Tiam1, Rac1 and JNK in cortical neuronal migration.

    • Author(s)
      Kawauchi T
    • Journal Title

      EMBO J.2003 Aug 22(16)

      Pages: 4190-4201

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Impaired negative feedback suppression of bile acid synthesis in mice lacking βKlotho.

    • Author(s)
      Ito S.
    • Journal Title

      J.Clin.Invest. (in press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Patent(Industrial Property Rights)] βKlotho遺伝子、Cyp7a1遺伝子、及びそれらの利用2004

    • Inventor(s)
      鍋島 陽一, 伊藤 慎二, 鍋島 曜子, 藤森 俊彦
    • Industrial Property Rights Holder
      京都大学医学TLO
    • Industrial Property Number
      2004-357395
    • Filing Date
      2004-12-09
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Patent(Industrial Property Rights)] クロソ蛋白質の酵素活性の測定法及びその利用2003

    • Inventor(s)
      鍋島 陽一, 遠山 修
    • Industrial Property Rights Holder
      科学技術振興機構
    • Industrial Property Number
      2003-146953
    • Filing Date
      2003-05-23
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Publications] Nagai T., Yamada K., Kim H-C., Kim Y-S., Noda Y, Imura A., Nabeshima Y., Nabeshima T.: "Cognition impairment in the genetic model of aging, Klotho gene mutant mice : A role of oxidative stress."Faseb J.. 17(1). 50-52 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yang J., Matssukawa N., Rakugi H., Imai M., Kida I., Nagai M., Ohta J., Fukuo K., Nabeshima Y., Ogihara T.: "Upregulation of cAMP is a new functional signal pathway of Klotho in endotherial cells."Biochem.Biophys.Res.Comm.. 301(2). 424-429 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yahata K, Mori K, Mukoyama M, Sugawara A, Suganami T, Makino H, Nagae T, Fujinaga Y, Nabeshima Y, Nakao K.: "Regulation of stanniocalcin 1 and 2 expression in the kidney by klotho gene."Biochem Biophys Res Commun.. 310(1). 128-134 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Toyama O., Imura A., Iwano A., Jean Noel Freund, Henrissat B., Fujimori T., Nabeshima Y.: "Klotho is a novel β-glucuronidase capable of hydrolyzing steroid β-glucuronides."J.Biol.Chem.. 279(11). 9777-9784 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Tsujikaw H., Kurotaki Y., Fujimori T., Fukuda K., Nabeshima Y.: "Klotho, a gene related to a syndrome resembling human premature aging, functions in a negative regulatory circuit of vitamin D endocrine system."Molecular Endcrinology. 17(12). 2393-2403 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] K Takeshita, T Fujimori, Y Kurotaki, H Honjo, Hiroshi Tsujikawa, K Yasui, J-K Lee, K Kamiya, K Kitaichi, K Yamamoto, M Ito, T Kondo, S Iino, Y Inden, M Hirai, T Murohara, I Kodama, Y.Nabeshima: "Sinoatrial Node Dysfunction and Early Unexpected Death of Mice with a Defect of Klotho Gene Expression."Circulation. (In press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Imura A., Iwano A., Kita N., Thoyama O., Fujimori T., Nabeshima Y.: "Secreted Klotho protein in sera and CSF : Implication for posttranslational cleavage in release of Klotho protein from cell membrane."FEBS letters. (In press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yoshida T., Fujimori T., Nabeshima Y.: "Mediation of unusually high concentrations of 1,25-dihydroxyvitamin D3 in homozygous klotho mutant mice by increased expression of renal lalpha-hydroxylase gene"Endocrinology. 143. 683-689 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Ito S., Fujimori T., Hayashizaki Y., Nabeshima Y.: "Identification of a novel mouse membrane-bound family 1 glycosidase-like protein, which carries an atypical active site structure"Biochem.Biophys.Acta. 1576(3). 341-345 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kashimada K., Yamashita T., Tsuji K., Nifuji A., Mizutani S., Nabeshima Y., Noda M.: "Defects in growth and bone metabolism in klotho mutant mice are resistant to growth hormone treatment"J.Endcrinology. 174(3). 403-410 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Manya H., Fujimori T., Nabeshima Y., Endo T.: "Klotho protein deficiency leads to overactivation of (Mu)-calpain"J.Biol.Chem.. 277(38). 35503-35508 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kawano K., Ogata N., Chiano M., Molloy H., Kleyn P., Spector T.D., Uchino M., Hosoi T., Suzuki T., Orimo H., Inoue S., Nabeshima Y., Nakamura K., Kuro-o M., Kawaguchi H.: "Klotho gene polymorphisms associated with bone density of aged postmenopausal women"J.Bone and Mineral Res. 17(10). 1744-1751 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yamashita T, Okada S, Higashio K, Nabeshima Y, Noda M.: "Double mutations in klotho and osteoprotegerin gene loci rescued osteopetrotic phenotype"Endocrinology. 143(12). 4711-4717 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Takeshita K., Yamamoto K., Ito M., Kondo T., Matsushita T., Hirai M., Kojima T., Nishimura M., Nabeshima Y., Loskutoff D.J., Saito H., Murohara T.: "Increased expression of plasminogen activator inhibitor-1 with fibrin deposition in a murine model of aging, Klotho mouse"Semin Thromb Hemost.. 28(6). 545-553 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Nagai T., Yamada K., Kim H-C., Kim Y-S., Noda Y., Imura A., Nabeshima Y., Nabeshima T.: "Cognition impairment in the genetic model of aging, klotho gene mutant mice : A role of oxidative stress"Faseb J.. 17(1). 50-52 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yang J., Matssukawa N., Rakugi H., Imai M., Kida I., Nagai M., Ohta J., Fukuo K., Nabeshima Y., Ogihara T.: "Upregulation of cAMP is a new functional signal pathway of Klotho in endotherial cells"Biochem.Biophys.Res.Comm.. 301(2). 424-429 (2003)

    • Related Report
      2002 Annual Research Report

URL: 

Published: 2002-04-01   Modified: 2016-04-21  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi