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Proteomic analysis of the pathogenesis of proteinuria and nephrotic syndrome.

Research Project

Project/Area Number 19390281
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Pediatrics
Research InstitutionThe University of Tokyo

Principal Investigator

IGARASHI Takashi  The University of Tokyo, 医学部附属病院, 教授 (70151256)

Co-Investigator(Kenkyū-buntansha) SEKINE Takashi  東邦大学, 医学部附属病院・大橋病院, 教授 (50255402)
張田 豊  横浜市立大学, 生命ナノシステム科学研究科, 特任助教 (10451866)
Co-Investigator(Renkei-kenkyūsha) HARITA Yutaka  横浜市立大学, 生命ナノシステム科学研究科, 特任助教 (10451866)
Project Period (FY) 2007 – 2009
Project Status Completed (Fiscal Year 2009)
Budget Amount *help
¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000)
Fiscal Year 2009: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
Fiscal Year 2008: ¥8,190,000 (Direct Cost: ¥6,300,000、Indirect Cost: ¥1,890,000)
Fiscal Year 2007: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Keywordsネフローゼ症候群 / 蛋白尿 / プロテオミクス / 腎臓 / 糸球体上皮細胞 / Nephrin / TRPC6 / MYN9 / Epstein-Fechtner症候群 / プロテオーム / ネフローゼ / 細胞内情報伝達 / ネフリン / ポドサイト
Research Abstract

A specialized intercellular junction between podocytes, known as the slit diaphragm, forms the essential structural framework for glomerular filtration in the kidney. In this study, we performed proteomic analysis to characterize the structure and function of slit diaphragm as a signaling complex. We found that post-translational modification orchestrates a wide spectrum of protein-protein interactions and intracellular signaling networks at slit diaphragm. These results unraveled the role of dynamics of slit diaphragm signal complex in modulating the glomerular filtration barrier function. We also performed genetic studies on Epstein and Fechtner syndromes which often develops progressive nephrotic syndrome, and found that R702 mutations display a strict genotype-phenotype correlation, and lead to the rapid deterioration of podocyte structure. Our results highlight the critical role of functional podocyte molecules in the development of Nephrotic syndrome.

Report

(4 results)
  • 2009 Annual Research Report   Final Research Report ( PDF )
  • 2008 Annual Research Report
  • 2007 Annual Research Report
  • Research Products

    (52 results)

All 2010 2009 2008 2007 Other

All Journal Article (30 results) (of which Peer Reviewed: 16 results) Presentation (18 results) Book (4 results)

  • [Journal Article] Patients with Epstein-Fechtner syndromes owing to MYH9 R702 mutations develop progressive proteinuric renal disease.2010

    • Author(s)
      Sekine T, Konno M, Sasaki S, et al.
    • Journal Title

      Kidney International (In press)

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Glomerular proteins related to slit diaphragm and matrix adhesion in the foot processes are highly tyrosine phosphorylated in the normal rat kidney.2010

    • Author(s)
      Zhang Y, Yoshida Y, Nameta M, et al.
    • Journal Title

      Nephrol Dial Transplant. (In press)

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Salt-losing nephrogenic diabetes insipidus caused by fetal exposure to angiotensin receptor blocker.2009

    • Author(s)
      Miura K, Sekine T, Iida A, et al
    • Journal Title

      Pediatric Nephrology 24

      Pages: 1235-8

    • Related Report
      2009 Final Research Report
    • Peer Reviewed
  • [Journal Article] Phosphorylation of Nephrin Triggers Ca2+ Signaling by Recruitment and Activation of Phospholipase C-γ1.2009

    • Author(s)
      Harita Y, Kurihara H, Kosako H, Tezuka T, Sekine T, Igarashi T, Ohsawa I, Ohta S, Hattori S
    • Journal Title

      J Biol Chem 284

      Pages: 8951-62

    • Related Report
      2009 Final Research Report
    • Peer Reviewed
  • [Journal Article] 特集-プロテオミクスが解き明かす情報伝達ネットワーク:腎糸球体上皮細胞におけるチロシンキナーゼシグナリング2009

    • Author(s)
      張田豊
    • Journal Title

      実験医学(羊土社) Vol.27

      Pages: 2582-2587

    • Related Report
      2009 Final Research Report
  • [Journal Article] 腎における細胞内シグナル伝達と病態生理:細胞機能のスイッチとしての蛋白質リン酸化・脱リン酸化2009

    • Author(s)
      張田豊
    • Journal Title

      腎と透析(東京医学社) Vol.67

      Pages: 300-305

    • Related Report
      2009 Final Research Report
  • [Journal Article] 遺伝性ネフローゼ症候群の原因解析からみる濾過バリアとしてのpodocyte2009

    • Author(s)
      張田豊
    • Journal Title

      小児内科 Vol.41,No.2

      Pages: 252-256

    • Related Report
      2009 Final Research Report
  • [Journal Article] 糸球体上皮細胞の新たな情報伝達分子と新機能2009

    • Author(s)
      張田豊
    • Journal Title

      Annual Review腎臓2009(中外医学社)

      Pages: 1-7

    • Related Report
      2009 Final Research Report
  • [Journal Article] 爪膝蓋骨症候群2009

    • Author(s)
      五十嵐隆
    • Journal Title

      専門医のための腎臓病学(医学書院)

      Pages: 367-370

    • Related Report
      2009 Final Research Report
  • [Journal Article] Dent病2009

    • Author(s)
      五十嵐隆
    • Journal Title

      専門医のための腎臓病学(医学書院)

      Pages: 549-553

    • NAID

      10029736392

    • Related Report
      2009 Final Research Report
  • [Journal Article] Gitelman症候群2009

    • Author(s)
      五十嵐隆
    • Journal Title

      専門医のための腎臓病学(医学書院)

      Pages: 553-555

    • Related Report
      2009 Final Research Report
  • [Journal Article] Fanconi症候群2009

    • Author(s)
      五十嵐隆
    • Journal Title

      エキスパートのための腎臓内科学(中外医学社)

      Pages: 325-328

    • Related Report
      2009 Final Research Report
  • [Journal Article] Salt-losing nephrogenic diabetes insipidus caused by fetal exposure to angiotensin receptor blocker.2009

    • Author(s)
      Miura K, Sekine T, Iida A, et al.
    • Journal Title

      Pediatric Nephrology 24

      Pages: 1235-8

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 腎糸球体上皮細胞におけるチロシンキナーゼシグナリング2009

    • Author(s)
      張田豊
    • Journal Title

      実験医学 27

      Pages: 2582-2587

    • Related Report
      2009 Annual Research Report
  • [Journal Article] 細胞機能のスイッチとしての蛋白質リン酸化・脱リン酸化2009

    • Author(s)
      張田豊
    • Journal Title

      腎と透析 67

      Pages: 300-305

    • Related Report
      2009 Annual Research Report
  • [Journal Article] Neph1, a component of the kidney slit diaphragm, is tyrosine phosphorylated by Fyn and modulates intracellular signaling by binding to Grb2.2008

    • Author(s)
      Harita Y, Kurihara H, Kosako H, Tezuka T, Sekine T, Igarashi T, Hattori S
    • Journal Title

      J. Biol. Chem. 283

      Pages: 9177-86

    • Related Report
      2009 Final Research Report
    • Peer Reviewed
  • [Journal Article] Reevaluation of glomerular charge selective protein-sieving function.2008

    • Author(s)
      Saito H, Takahashi S, Nagata M, Tsuchiya T, Mugishima H, Yan K, Kondo Y, Matsuyama T, Sekine T, Igarashi T
    • Journal Title

      Pediatr Nephrol 24

      Pages: 609-612

    • NAID

      10024846587

    • Related Report
      2009 Final Research Report
    • Peer Reviewed
  • [Journal Article] Functional analysis of a novel missense NBC1 mutation and of othe mutations causing proximal renal tubular acidosis2008

    • Author(s)
      Suzuki M, Vaisbich MH, Yamada H, Horita S, Li Y, Sekine T, Moriyama N, Igarashi T, Endo Y, Cardoso TP, de Sa LC, Koch VH, Seki G, Fujita T
    • Journal Title

      Pflugers Arch-Eur J Physiol 455

      Pages: 583-593

    • Related Report
      2009 Final Research Report
    • Peer Reviewed
  • [Journal Article] 腎尿路疾患のABCと新たな展開-ネフローゼ症候群の病態2008

    • Author(s)
      張田豊
    • Journal Title

      小児科診療(診断と治療社) Vol.72,No.2

    • Related Report
      2009 Final Research Report
  • [Journal Article] 総説:糸球体上皮細胞、その構造と機能-蛋白尿の発症原因の解明に向けて-2008

    • Author(s)
      張田豊
    • Journal Title

      日本小児科学会雑誌 Vo;.112,No.8

      Pages: 1219-1226

    • Related Report
      2009 Final Research Report
    • Peer Reviewed
  • [Journal Article] Nephl, a component of the kidney slit diaphragm, is tyrosine-phosphorylated by the Src2008

    • Author(s)
      Harita Y, Sekine T, Igarashi, T, et al
    • Journal Title

      J Bioi Chem 283

      Pages: 9177-9186

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 糸球体上皮細胞、その構造と機能ム蛋白尿の発症原因の解明に向けて2008

    • Author(s)
      張田豊
    • Journal Title

      日本小児科学会雑誌 71

      Pages: 29-34

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 糸球体charge barrier機能の再検討2008

    • Author(s)
      斉藤宏、関根孝司、五十嵐隆、他
    • Journal Title

      日本小児腎臓病学会雑誌 21

      Pages: 55-59

    • NAID

      10024846587

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] lschemic colitis as a complication in a patient with steroid-dependent nephretic sydnrome2008

    • Author(s)
      Yanagisawa A, Sekine T, lgarashi T
    • Journal Title

      Pediatrc Nephrology 23

      Pages: 655-657

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] OCRL1 mutations in patients with Dent disease phenotype in Japan.2007

    • Author(s)
      Sekine T, Nozu K, Iyengar R, Fu XJ, Matsuo M, Tanaka R, Iijima K, Matsui E, Harita Y, Inatomi J, Igarashi T
    • Journal Title

      Pediatr. Nephrol. 22

      Pages: 975-980

    • Related Report
      2009 Final Research Report
  • [Journal Article] 蛋白尿発症機序解明に向けた研究の流れと今後の展望-糸球体上皮細胞におけるシグナル伝達系の役割-2007

    • Author(s)
      張田豊
    • Journal Title

      小児腎臓病学会雑誌 Vol.20,No.2

      Pages: 76-81

    • NAID

      10025701225

    • Related Report
      2009 Final Research Report
    • Peer Reviewed
  • [Journal Article] これだけは知っておきたい分子腎臓病学-PLC2007

    • Author(s)
      張田豊
    • Journal Title

      腎と透析(東京医学社) Vol63,No.4

      Pages: 542-545

    • Related Report
      2009 Final Research Report
  • [Journal Article] 糸球体血管壁を通過した蛋白の再吸収機序2007

    • Author(s)
      五十嵐 隆
    • Journal Title

      Nephrology Frontier 6

    • Related Report
      2007 Annual Research Report
  • [Journal Article] Patients with Epstein-Fechtner syndromes owing to MYH9 R702 mutations develop progressive proteinuric renal disease.

    • Author(s)
      Sekine T, Konno M, Sasaki S, et al
    • Journal Title

      Kidney International (in press)

    • Related Report
      2009 Final Research Report
    • Peer Reviewed
  • [Journal Article] Glomerular proteins related to slit diaphragm and matrix adhesion in the foot processes are highly tyrosine phosphorylated in the normal rat kidney.

    • Author(s)
      Zhang Y, Yoshida Y, Nameta M, Xu B, Taguchi I, Ikeda T, Fujinaka H, Mohamed SM, Tsukaguchi H, Harita Y, Yaoita E, Yamamoto T
    • Journal Title

      Nephrol Dial Transplant. (in press)

    • Related Report
      2009 Final Research Report
    • Peer Reviewed
  • [Presentation] SIRPαCo-Localizes with Nephrin at Podocyte Slit Diaphragm, and Modulates Nephrin Tyrosine Phosphorylation.2009

    • Author(s)
      Harita Y
    • Organizer
      ASN (American Society of Nephrology)Renal Week 2009
    • Place of Presentation
      San Diego, CA
    • Year and Date
      2009-10-31
    • Related Report
      2009 Final Research Report
  • [Presentation] Phosphorylation-dependent surface expression of TRPC6 by PLCg is negatively regulated by Nephrin.2009

    • Author(s)
      Kanda S, Harita Y, et al
    • Organizer
      ASN (American Society of Nephrology) Renal Week 2009
    • Place of Presentation
      San Diego, CA
    • Year and Date
      2009-10-30
    • Related Report
      2009 Final Research Report
  • [Presentation] SIRPα Co-Localizes with Nephrin at Podocyte Slit Diaphragm, and Modulates Nephrin Tyrosine Phosphorylation.2009

    • Author(s)
      Harita Y, Matsunaga A, Tsurumi, et al.
    • Organizer
      ASN Renal Week 2009
    • Place of Presentation
      San Diego, USA
    • Year and Date
      2009-10-30
    • Related Report
      2009 Annual Research Report
  • [Presentation] Phosphorylation-dependent surface expression of TRPC6 by PLCg is negatively regulated by Nephrin2009

    • Author(s)
      Kanda S, Harita Y, et al.
    • Organizer
      ASN Renal Week 2009
    • Place of Presentation
      San Diego, USA
    • Year and Date
      2009-10-30
    • Related Report
      2009 Annual Research Report
  • [Presentation] Molecular pathogenesis of primary renal tubular acidosis.2009

    • Author(s)
      Igarashi T
    • Organizer
      The 44th European Society of Pediatric nephrology
    • Place of Presentation
      Birmingham
    • Year and Date
      2009-09-05
    • Related Report
      2009 Final Research Report
  • [Presentation] 糸球体スリット膜におけるリン酸化シグナリング.2009

    • Author(s)
      張田豊
    • Organizer
      第24回新潟腎シンポジウム
    • Place of Presentation
      新潟
    • Year and Date
      2009-07-25
    • Related Report
      2009 Final Research Report
  • [Presentation] 糸球体スリット膜におけるリン酸化シグナリング.2009

    • Author(s)
      張田豊
    • Organizer
      第24回新潟腎シンポジウム,(講演)
    • Place of Presentation
      新潟
    • Year and Date
      2009-07-25
    • Related Report
      2009 Annual Research Report
  • [Presentation] Nephrinのチロシンリン酸化はPLCγ-1を介し細胞内Ca2+濃度を上昇させる.2009

    • Author(s)
      張田豊
    • Organizer
      第52回日本腎臓学会学術総会基礎と臨床の融合
    • Place of Presentation
      横浜
    • Year and Date
      2009-06-26
    • Related Report
      2009 Final Research Report
  • [Presentation] Nephrinのチロシンリン酸化はPLCY-1を介し細胞内Ca^<2+>濃度を上昇させる.2009

    • Author(s)
      張田豊
    • Organizer
      第52回日本腎臓学会学術総会
    • Place of Presentation
      横浜
    • Year and Date
      2009-06-04
    • Related Report
      2009 Annual Research Report
  • [Presentation] 先天性遺伝性ネフローゼ症候群の原因解析から見えてきた蛋白尿の発症機序.2009

    • Author(s)
      張田豊
    • Organizer
      第112回日本小児科学学会学術集会
    • Place of Presentation
      奈良
    • Year and Date
      2009-04-17
    • Related Report
      2009 Annual Research Report 2009 Final Research Report
  • [Presentation] TRPC6 as a possible link between Nephrin and PLCγ-the role of phosphorylation of TRPC6.2008

    • Author(s)
      Kanda S, Harita Y, Sekine T, Igarashi T, Hattori S
    • Organizer
      Renal Week 2008
    • Place of Presentation
      フィラデルフィア
    • Year and Date
      2008-11-06
    • Related Report
      2009 Final Research Report
  • [Presentation] Clustering-indiced phosphorylation of Nephrin triggers Ca2+ entry by recruitment and activation of PLCγ.2008

    • Author(s)
      Harita Y, Kurihara H, Kosako H, Tezuka T, Sekine T, Igarashi T, Ohsawa I, Ohta S, Hattori S
    • Organizer
      Renal Week 2008
    • Place of Presentation
      フィラデルフィア
    • Year and Date
      2008-11-06
    • Related Report
      2009 Final Research Report
  • [Presentation] Recruitment and activation of PLC-γ by phosphorylation of nephrin: a new insight into a link between slit diaphragm and calcium signaling.2008

    • Author(s)
      Harita Y, Kurihara H, Kosako H, Tezuka T, Sekine T, Igarashi T, Ohsawa I, Ohta S, Hattori S
    • Organizer
      7th International Podocyte Meeting
    • Place of Presentation
      トロント
    • Year and Date
      2008-06-04
    • Related Report
      2009 Final Research Report
  • [Presentation] Recruitment and activation of PLC-γ by phosphorylation of nephrin。2008

    • Author(s)
      Harita Y, et al
    • Organizer
      7th International Podocyte Meeting
    • Place of Presentation
      トロント
    • Year and Date
      2008-06-04
    • Related Report
      2008 Annual Research Report
  • [Presentation] ネフローゼ症候群の病態解明への挑戦と治療の標準化-ネフローゼ症候群発症に関連する分子群と蛋白尿発生メカニズム-2008

    • Author(s)
      張田豊
    • Organizer
      日本小児科学会(シンポジウム)
    • Place of Presentation
      東京
    • Year and Date
      2008-04-25
    • Related Report
      2009 Final Research Report
  • [Presentation] PLC-gamma as a novel phospho-nephrin binding protein2007

    • Author(s)
      Harita Y, Kurihara H, Kanda S, Sekine T, Igarashi T, Hattori S
    • Organizer
      Renal Week 2007
    • Place of Presentation
      サンフランシスコ
    • Year and Date
      2007-10-03
    • Related Report
      2009 Final Research Report
  • [Presentation] チロシンリン酸化による糸球体上皮細胞スリット膜複合体の機能制御2007

    • Author(s)
      張田 豊
    • Organizer
      第41回日本小児腎臓病学会(最優秀演題賞基礎部門賞・森田賞受賞)
    • Place of Presentation
      横浜市
    • Year and Date
      2007-06-29
    • Related Report
      2007 Annual Research Report
  • [Presentation] 糸球体上皮細胞スリット膜におけるシグナル伝達解析2007

    • Author(s)
      張田豊
    • Organizer
      第91回東京腎生理集団会
    • Place of Presentation
      東京
    • Year and Date
      2007-04-07
    • Related Report
      2009 Final Research Report
  • [Book] Fanconi syndrome, Pediatric Nephrology, 6th edition, vol 1, (Edited by Avner ED, Harmon WE, Niaudet P, Yoshikawa N)2009

    • Author(s)
      Igarashi T
    • Publisher
      Springer-Verlag
    • Related Report
      2009 Final Research Report
  • [Book] 小児腎疾患の臨床、改訂第3版2008

    • Author(s)
      五十嵐隆
    • Total Pages
      291
    • Publisher
      診断と治療社
    • Related Report
      2009 Final Research Report
  • [Book] 小児腎疾患の臨床(改訂第3版)2008

    • Author(s)
      五十嵐隆
    • Total Pages
      291
    • Publisher
      診断と治療社
    • Related Report
      2008 Annual Research Report
  • [Book] 小児腎疾患の臨床(改訂第2版)2007

    • Author(s)
      五十嵐 隆
    • Total Pages
      277
    • Publisher
      診断と治療社
    • Related Report
      2007 Annual Research Report

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Published: 2007-04-01   Modified: 2016-04-21  

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