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

Targeting macrophage pinocytosis in atherosclerosis

Research Project

Project/Area Number 15K09418
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Metabolomics
Research InstitutionShowa University

Principal Investigator

Miyazaki Takuro  昭和大学, 医学部, 講師 (80398693)

Project Period (FY) 2015-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2015: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Keywords動脈硬化症 / 生活習慣病 / コレステロール / マクロファージ / タンパク質分解 / カルパイン / 動脈硬化 / mRNAスプライシング / エキソン接合部複合体 / 飲作用 / CWC22 / エクソンジャンクション複合体 / pre-mRNAスプライシング / カルパイン-6
Outline of Final Research Achievements

We have investigated calpain proteolytic systems as a therapeutic target of the diseases, such as atherosclerosis, tumor angiogenesis and retinopathy. Calpains are intracellular calcium-dependent proteases, which contributes to the proteolytic processing of the target proteins thereby regulating cellular processes, such as inflammatory processes and cellular dynamics. Herein, we investigated the proatherogenic roles of calpain-6, an atypical non-proteolytic calpain member. It appears that calpain-6 disturbs mRNA splicing process of Rac1 by interfering with CWC22/exon junction complexes, resulting in the impaired pinocytotic incorporation of native LDL in macrophages. Accordingly, over expression of calpain-6 in macrophages aggravates atherosclerosis. In addition, our data showed that the contribution of calpain-6 in adipose stromal macrophages to obesity.

Academic Significance and Societal Importance of the Research Achievements

現行の動脈硬化症の病態生理学は、マクロファージがスカベンジャー受容体依存的に酸化LDLを取込むことで泡沫化し、動脈硬化病変が形成される、いわゆる「酸化LDL仮説」に基づく。しかし、生体内に存在する LDL の多くはスカベンジャー受容体が認識するほど高度に酸化されておらず、同仮説だけでは実際に血管壁で起こるマクロファージ泡沫化を合理的に説明することはできなかった。本研究を通して、受容体非依存的なピノサイトーシス経路の一端が明らかとなり、マクロファージコレステロール代謝異常解明の一助となることが期待される。

Report

(5 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • 2015 Research-status Report
  • Research Products

    (48 results)

All 2019 2018 2017 2016 2015 Other

All Journal Article (16 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 16 results,  Open Access: 9 results,  Acknowledgement Compliant: 2 results) Presentation (22 results) (of which Int'l Joint Research: 4 results,  Invited: 12 results) Remarks (10 results)

  • [Journal Article] Endothelial calpain systems orchestrate myofibroblast differentiation during wound healing.2019

    • Author(s)
      Miyazaki T, Haraguchi S, Kim-Kaneyama JR, Miyazaki A.
    • Journal Title

      FASEB Journal

      Volume: 33 Issue: 2 Pages: 2037-2046

    • DOI

      10.1096/fj.201800588rr

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Thrombolytic Therapy for Acute Ischemic Stroke: Past and Future.2019

    • Author(s)
      Shibata K, Hashimoto T, Miyazaki T, Miyazaki A, Nobe K.
    • Journal Title

      Curr Pharm Des

      Volume: in press Issue: 3 Pages: 242-250

    • DOI

      10.2174/1381612825666190319115018

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] L-Leucine increases the daily body temperature and affords thermotolerance in broiler chicks.2019

    • Author(s)
      Han G, Yang H, Wang Y, Haraguchi S, Miyazaki T, Bungo T, Tashiro K, Furuse M, Chowdhury VS
    • Journal Title

      Asian-Australas J Anim Sci

      Volume: in press Issue: 6 Pages: 842-848

    • DOI

      10.5713/ajas.18.0677

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Evaluation of protein-protein interactions using an on-membrane digestion technique.2019

    • Author(s)
      Obama T, Miyazaki T, Aiuchi T, Miyazaki A, Itabe H
    • Journal Title

      J Vis Exp

      Volume: in press

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Dysregulation of Calpain Proteolytic Systems Underlies Degenerative Vascular Disorders2018

    • Author(s)
      Miyazaki T, Miyazaki A.
    • Journal Title

      Journal of Atherosclerosis and Thrombosis

      Volume: 25 Issue: 1 Pages: 1-15

    • DOI

      10.5551/jat.RV17008

    • NAID

      130006301106

    • ISSN
      1340-3478, 1880-3873
    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] The impact of stromal Hic-5 on the tumorigenesis of colorectal cancer through lysyl oxidase induction and stromal remodeling.2018

    • Author(s)
      Omoto T, Kim-Kaneyama JR, Lei XF, Orimo A, Ohnishi K, Yoshihara K, Miyauchi A, Li S, Gao L, Umemoto T, Tanaka J, Nakahara K, Takeya M, Ishida F, Kudo SE, Haraguchi S, Miyazaki T, Miyazaki A.
    • Journal Title

      Oncogene.

      Volume: 37 Issue: 9 Pages: 1205-1219

    • DOI

      10.1038/s41388-017-0033-y

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Expression of steroidogenic enzymes and metabolism of steroids in COS-7 cells known as non-steroidogenic cells.2018

    • Author(s)
      Nozaki M, Haraguchi S, Miyazaki T, Shigeta D, Kano N, Lei XF, Kim-Kaneyama JR, Minakata H, Miyazaki A, Tsutsui K.
    • Journal Title

      Sci Rep.

      Volume: 8 Issue: 1 Pages: 2167-2167

    • DOI

      10.1038/s41598-018-20226-2

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Impact of dysfunctional protein catabolism on macrophage cholesterol handling.2018

    • Author(s)
      Miyazaki T, Miyazaki A.
    • Journal Title

      Curr Med Chem.

      Volume: 印刷中 Issue: 9 Pages: 1631-1643

    • DOI

      10.2174/0929867325666180326165234

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Emerging roles of calpain proteolytic systems in macrophage cholesterol handling.2017

    • Author(s)
      Miyazaki T and Miyazaki A
    • Journal Title

      Cellular and molecular life science

      Volume: 印刷中 Issue: 16 Pages: 3011-3021

    • DOI

      10.1007/s00018-017-2528-7

    • Related Report
      2017 Research-status Report 2016 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Defective protein catabolism in atherosclerotic vascular inflammation.2017

    • Author(s)
      Miyazaki T, Miyazaki A.
    • Journal Title

      Front Cardiovasc Med.

      Volume: 4 Pages: 79-79

    • DOI

      10.3389/fcvm.2017.00079

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Functional Heterogeneity of Nadph Oxidases in Atherosclerotic and Aneurysmal Diseases2017

    • Author(s)
      Kigawa Y, Miyazaki T, Lei XF, Kim-Kaneyama JR, Miyazaki A.
    • Journal Title

      Journal of Atherosclerosis and Thrombosis

      Volume: 24 Issue: 1 Pages: 1-13

    • DOI

      10.5551/jat.33431

    • NAID

      130005188266

    • ISSN
      1340-3478, 1880-3873
    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Proteolytic inactivation of anti-angiogenic vasohibin-1 by cancer cells.2016

    • Author(s)
      Saito M, Suzuki Y, Yano S, Miyazaki T, Sato Y.
    • Journal Title

      Journal of biochemistry

      Volume: 160 Issue: 4 Pages: 227-232

    • DOI

      10.1093/jb/mvw030

    • NAID

      40020980740

    • Related Report
      2016 Research-status Report
    • Peer Reviewed
  • [Journal Article] Calpain-6 confers atherogenicity to macrophages by dysregulating pre-mRNA splicing.2016

    • Author(s)
      Miyazaki T, Tonami K, Hata S, Aiuchi T, Ohnishi K, Lei XF, Kim-Kaneyama JR, Takeya M, Itabe H, Sorimachi H, Kurihara H, Miyazaki A
    • Journal Title

      J Clin Invest

      Volume: 126 Issue: 9 Pages: 3417-3432

    • DOI

      10.1172/jci85880

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Hic-5 deficiency attenuates the activation of hepatic stellate cells and liver fibrosis through upregulation of Smad7 in mice2016

    • Author(s)
      Xiao-Feng Lei, Wenguang Fu, Joo-ri Kim-Kaneyama, Tomokatsu Omoto, Takuro Miyazaki, Bo Li, Akira Miyazaki
    • Journal Title

      Journal of Hepatology

      Volume: 64 Issue: 1 Pages: 110-117

    • DOI

      10.1016/j.jhep.2015.08.026

    • Related Report
      2016 Research-status Report 2015 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Calpastatin counteracts pathological angiogenesis by inhibiting suppressor of cytokine signaling 3 degradation in vascular endothelial cells.2015

    • Author(s)
      Miyazaki, T., Taketomi, Y., Saito, Y., Hosono, T., Lei, X.F., Kim-Kaneyama, J.R., Arata, S., Takahashi, H., Murakami, M., and Miyazaki, A.
    • Journal Title

      Circ. Res.

      Volume: 116 Issue: 7 Pages: 1170-1181

    • DOI

      10.1161/circresaha.116.305363

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Role of HIC-5 in the formation of microvilli-like structures and the monocyte-endotherial interaction that accelerates atherosclerosis2015

    • Author(s)
      Shigeko Arita-Okubo, et al
    • Journal Title

      Cardiovasc Res

      Volume: 105 Issue: 3 Pages: 361-371

    • DOI

      10.1093/cvr/cvv003

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] しなやかな血管を手に入れる2019

    • Author(s)
      宮崎拓郎
    • Organizer
      東京都目黒区 平成31年健康大学第1回教養講座
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] タンパク質をマスターして健康な体になろう! 血管変性疾患への挑戦:しなやかな血管を手にいれる2018

    • Author(s)
      宮崎拓郎
    • Organizer
      東京都医学総合研究所第1回都民講座
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] Endothelial calpain systems orchestrate myofibroblast differentiation during wound healing2018

    • Author(s)
      Miyazaki T, Haraguchi S, Kim-Kaneyama JR, Miyazaki A
    • Organizer
      The 20th International Vascular Biology Meeting
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] カルパインプロテアーゼファミリーによる血管系疾患の制御.2018

    • Author(s)
      宮崎拓郎・宮崎章
    • Organizer
      第50回日本動脈硬化学会学術集会 合同シンポジウム2 日本血管生物医学会合同シンポジウム
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] 動脈硬化病変マクロファージに潜むタンパク質分解機構の制御不全2018

    • Author(s)
      宮崎拓郎・宮崎章
    • Organizer
      第50回日本動脈硬化学会学術集会Cutting-Edge Symposium 9 マクロファージ研究の最前線
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] マクロファージ動脈硬化原性を制御する細胞内プロテアーゼシステム.2018

    • Author(s)
      宮崎拓郎
    • Organizer
      第33回日本糖尿病合併症学会 シンポジウム2
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] タンパク質恒常性低下を起点とした動脈硬化発症機構.2018

    • Author(s)
      宮崎拓郎
    • Organizer
      第26回日本血管生物医学会学術集会 シンポジウム2 「血管炎症機転と動脈硬化症(日本動脈硬化学会共催シンポジウム)」
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] Regulation of atherosclerosis by calpain proteolytic systems2018

    • Author(s)
      Takuro Miyazaki
    • Organizer
      Spring Conference of the Korean Society of Lipid and Atherosclerosis 2018 Symposium 1: Vascular Inflammation and Remodeling
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] 動脈硬化病変マクロファージの飲作用を介したLDLコレステロール取込み機構2017

    • Author(s)
      宮崎 拓郎、雷 小峰、金山 朱里、宮崎 章
    • Organizer
      第59回 日本脂質生化学会
    • Related Report
      2017 Research-status Report
  • [Presentation] 血管系疾患に潜む制御性プロテアーゼの機能不全2017

    • Author(s)
      宮崎 拓郎
    • Organizer
      第67回NCVC研究者交流会
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] カルパインファミリーは動脈硬化病変を制御する2017

    • Author(s)
      宮崎 拓郎、礪波 一夫、秦 勝志、相内 敏弘、大西 紘二、雷 小峰、金山 朱里、竹屋 元裕、板部 洋之、反町 洋之、栗原 裕基、宮崎 章
    • Organizer
      2017年度生命科学系学会合同年次大会
    • Related Report
      2017 Research-status Report
  • [Presentation] Disturbance of pre-mRNA splicing by calpain-6 aggravates macrophage cholesterol deposition in atherosclerotic lesions2016

    • Author(s)
      宮崎 拓郎
    • Organizer
      第24回血管生物医学会学術集会
    • Place of Presentation
      長崎ブリックホール
    • Year and Date
      2016-12-09
    • Related Report
      2016 Research-status Report
  • [Presentation] Calpain-6 potentiates pro-atherogenic pinocytosis in macrophages2016

    • Author(s)
      宮崎 拓郎
    • Organizer
      19th International vascular biology meeting
    • Place of Presentation
      Sheraton Boston Hotel (U.S.A.)
    • Year and Date
      2016-11-01
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] Calpain proteolytic systems in atherosclerotic and aneurysmal diseases2016

    • Author(s)
      宮崎 拓郎
    • Organizer
      第48回日本動脈硬化学会学術集会
    • Place of Presentation
      京王プラザホテル(東京)
    • Year and Date
      2016-07-15
    • Related Report
      2016 Research-status Report
    • Invited
  • [Presentation] カルパインー6はmRNAの成熟不全を介してマクロファージLDL取込みを促進する2016

    • Author(s)
      宮崎 拓郎
    • Organizer
      第58回脂質生化学会大会
    • Place of Presentation
      秋田市にぎわい交流館AU
    • Year and Date
      2016-06-09
    • Related Report
      2016 Research-status Report
  • [Presentation] カルパインによるタンパク質プロセシングと動脈硬化症2016

    • Author(s)
      宮崎 拓郎
    • Organizer
      第45回日本心脈管作動物質学会年会
    • Place of Presentation
      阿波観光ホテル
    • Year and Date
      2016-02-05
    • Related Report
      2015 Research-status Report
    • Invited
  • [Presentation] カルパインシステムによるJAK/STAT経路依存的な病的血管新生の制御2015

    • Author(s)
      宮崎 拓郎、武富 芳隆、雷 小峰、金山 朱里、村上 誠、宮崎 章
    • Organizer
      BMB2015(日本分子生物学会 日本生化学会合同大会)
    • Place of Presentation
      神戸ポートアイランド
    • Year and Date
      2015-12-02
    • Related Report
      2015 Research-status Report
  • [Presentation] カルパインシステムによる血管系疾患の制御2015

    • Author(s)
      宮崎 拓郎
    • Organizer
      第 20 回日本病態プロテアーゼ学会学術集会
    • Place of Presentation
      ANAクラウンプラザホテルグランコート名古屋
    • Year and Date
      2015-08-22
    • Related Report
      2015 Research-status Report
    • Invited
  • [Presentation] カルパインシステムによる血管系疾患の制御2015

    • Author(s)
      宮崎 拓郎
    • Organizer
      The 16th Atherosclerosis and Biolipid Conference
    • Place of Presentation
      ホテル日航東京
    • Year and Date
      2015-08-01
    • Related Report
      2015 Research-status Report
    • Invited
  • [Presentation] カルパインシステムによるJAK/STAT経路依存的な病的血管新生の制御2015

    • Author(s)
      宮崎 拓郎、雷 小峰、金山 朱里、宮崎 章
    • Organizer
      第47回日本動脈硬化学会学術集会
    • Place of Presentation
      仙台国際センター
    • Year and Date
      2015-07-10
    • Related Report
      2015 Research-status Report
  • [Presentation] カルパイン-6によるマクロファージ飲作用・LDL取込ならびに動脈硬化病変の制御2015

    • Author(s)
      宮崎 拓郎、雷 小峰、金山 朱里、宮崎 章
    • Organizer
      第57回 日本脂質生化学会大会
    • Place of Presentation
      一橋大学一橋講堂
    • Year and Date
      2015-05-29
    • Related Report
      2015 Research-status Report
  • [Presentation] Calpastatin counteracts pathological angiogenesis by inhibiting suppressor of cytokine signalling 3 degradation in vascular endothelial cells2015

    • Author(s)
      Takuro Miyazaki, Yoshitaka Taketomi, Yuta Saito, Tomohiko Hosono, Xiao-Feng Lei, Joo-ri Kim-Kaneyama, Satoru Arata, Haruo Takahashi, Makoto Murakami, Akira Miyazaki
    • Organizer
      ISA2015 (XVII International Symposium on Atherosclerosis)
    • Place of Presentation
      Amsterdam RAI
    • Year and Date
      2015-05-24
    • Related Report
      2015 Research-status Report
    • Int'l Joint Research
  • [Remarks] 宮崎 拓郎(Takuro Miyazaki, PhD)

    • URL

      http://www10.showa-u.ac.jp/~biochem/Takuro_Miyazaki/Takuro_Miyazaki.html

    • Related Report
      2018 Annual Research Report
  • [Remarks] Research gate (Takuro Miyazaki)

    • URL

      https://www.researchgate.net/profile/Takuro_Miyazaki2

    • Related Report
      2018 Annual Research Report 2017 Research-status Report
  • [Remarks] Researchmap Takuro Miyazaki

    • URL

      https://researchmap.jp/miyazakitakuro/?lang=japanese

    • Related Report
      2018 Annual Research Report
  • [Remarks] Calpain-6 mediates atherogenic macrophage function

    • URL

      https://www.youtube.com/watch?v=VBdSyEDR5DU

    • Related Report
      2018 Annual Research Report 2017 Research-status Report
  • [Remarks] 宮崎 拓郎(Takuro Miyazaki, PhD)

    • URL

      http://www10.showa-u.ac.jp/~biochem/Takuro_Miyazaki/Takuro_Miyazaki.html

    • Related Report
      2017 Research-status Report
  • [Remarks] 昭和大学医学部生化学講座ホームページ

    • URL

      http://www10.showa-u.ac.jp/~biochem/Takuro_Miyazaki/Takuro_Miyazaki.html

    • Related Report
      2016 Research-status Report
  • [Remarks] 論文紹介ムービー(J Clin Invest. 2016;126:3417-3432.)

    • URL

      https://youtu.be/VBdSyEDR5DU

    • Related Report
      2016 Research-status Report
  • [Remarks] 昭和大学医学部生化学教室ホームページ

    • URL

      http://www10.showa-u.ac.jp/%7Ebiochem/Biochem/Biochem_top.html

    • Related Report
      2015 Research-status Report
  • [Remarks] Researchgate - Takuro Miyazaki

    • URL

      https://www.researchgate.net/profile/Takuro_Miyazaki2

    • Related Report
      2015 Research-status Report
  • [Remarks] Researchmap - 宮崎拓郎

    • URL

      http://researchmap.jp/miyazakitakuro/?lang=japanese

    • Related Report
      2015 Research-status Report

URL: 

Published: 2015-04-16   Modified: 2020-03-30  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi