Elucidation of the molecular pathogenesis of pulmonary hypertension via inflammatory cytokines
Project/Area Number |
16H05298
|
Research Category |
Grant-in-Aid for Scientific Research (B)
|
Allocation Type | Single-year Grants |
Section | 一般 |
Research Field |
Cardiovascular medicine
|
Research Institution | National Cardiovascular Center Research Institute |
Principal Investigator |
NAKAOKA YOSHIKAZU 国立研究開発法人国立循環器病研究センター, 研究所, 部長 (90393214)
|
Research Collaborator |
SHIRAI MIKIYASU
|
Project Period (FY) |
2016-04-01 – 2019-03-31
|
Project Status |
Completed (Fiscal Year 2018)
|
Budget Amount *help |
¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000)
Fiscal Year 2018: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2017: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Fiscal Year 2016: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
|
Keywords | 肺高血圧症 / 肺動脈性肺高血圧症(PAH) / 炎症 / 炎症性サイトカイン / インターロイキン6 / インターロイキン21 / 血管リモデリング / 肺動脈性肺高血圧症 / サイトカイン / IL-6 / IL-21 / エンドセリン受容体拮抗薬 / 血管保護 / interleukin-6 / interleukin-21 / 叢状病変 |
Outline of Final Research Achievements |
Pulmonary arterial hypertension (PAH) is a severe disease which causes stenosis and occlusion in the pulmonary small arteries and arterioles, leading to elevation of pulmonary arterial pressure due to unknown etiology. Since PAH patients might eventually result in right heart failure and death without adequate treatment, PAH is designated as an intractable disease by MHLW.We need to develop a novel therapeutic strategy for PAH which is distinct from the anti-PAH vaso-dilating agents. We identified IL-21 as a downstream target of IL-6 responsible for promoting the pathogenesis of HPH(PNAS.112: E2677, 2015).In this study, we tried to validate the effect of either IL-6 blockade or IL-21 blockade on the pathogenesis of PAH in a more severe animal model, namely the Sugen5416(Su)/Hypoxia/Normoxia (Su/Hx) rat model. We found that both IL-6 knockout and IL-21 receptor knockout rats showed significant resistance to severe PAH compared with conrol wild-type rats.
|
Academic Significance and Societal Importance of the Research Achievements |
これまでの遺伝子改変動物での肺高血圧症の病態研究は、低酸素誘発性肺高血圧症モデルマウスの系で遺伝子欠損マウスを用いて主に行われてきた。本研究ではCRISPR/Cas9システムを用いて、炎症性サイトカインのIL-6やIL-21受容体をノックアウトして、現在の最も重症な肺高血圧症モデルであるSugen5416/低酸素重症肺高血圧症モデルラットの系で、IL-6欠損、IL-21受容体欠損の効果を検討した。その結果、炎症性サイトカインの阻害によって肺高血圧症の重症化は顕著に抑制されて、炎症性サイトカイン阻害は新しい肺高血圧症に対する治療法の開発に繋がると期待されて、臨床的意義は大きいと考えられる。
|
Report
(4 results)
Research Products
(54 results)
-
-
-
-
[Journal Article] Genetic determinants and an epistasis of LILRA3 and HLA-B*52 in Takayasu arteritis.2018
Author(s)
Terao C, Yoshifuji H, Matsumura T, Naruse TK, Ishii T, Nakaoka Y, Kirino Y, Matsuo K, Origuchi T, Shimizu M, Maejima Y, Amiya E, Tamura N, Kawaguchi T, Takahashi M, Setoh K, Ohmura K, Watanabe R, Horita T, Atsumi T, Matsukura M, Miyata T, et al.
-
Journal Title
Proc Natl Acad Sci U S A
Volume: 115
Issue: 51
Pages: 13045-13050
DOI
Related Report
Peer Reviewed / Open Access
-
-
-
-
-
[Journal Article] Efficacy and safety of tocilizumab in patients with refractory Takayasu arteritis: results from a randomised, double-blind, placebo-controlled, phase 3 trial in Japan (the TAKT study).2018
Author(s)
2.Nakaoka Y, Isobe M, Takei S, Tanaka Y, Ishii T, Yokota S, Nomura A, Yoshida S, Nishimoto N.
-
Journal Title
Ann Rheum Dis.
Volume: 77
Issue: 3
Pages: 348-354
DOI
Related Report
Peer Reviewed / Open Access
-
-
-
-
[Journal Article] An EP4 Receptor Agonist Inhibits Cardiac Fibrosis Through Activation of PKA Signaling in Hypertrophied Heart2017
Author(s)
Wang Q,Oka T,Yamagami K,Lee JK,Akazawa H,Naito AT,Yasui T,Ishizu T,Nakaoka Y,Sakata Y,Komuro I.
-
Journal Title
International Heart Journal
Volume: 58
Issue: 1
Pages: 107-114
DOI
NAID
ISSN
1349-2365, 1349-3299
Related Report
Peer Reviewed / Open Access
-
[Journal Article] Molecular Characterization of Striated Muscle-specific Gab1Isoform as aCritical Signal Transducer for Neuregulin-1/ErbB Signaling in Cardiomyocytes.2016
Author(s)
Yasui T,Masaki T,Arita Y,Ishibashi T,Inagaki T,Okazawa M,Oka T,Shioyama W,Yamauchi-Takihara K,Komuro I,Sakata Y,Nakaoka Y.
-
Journal Title
PlosOne
Volume: 11
Issue: 11
Pages: e0166710-e0166710
DOI
Related Report
Peer Reviewed / Open Access / Acknowledgement Compliant
-
[Journal Article] Amelioration of sepsis by TIE2 activation-induced vascular protection.2016
Author(s)
Han S,Lee SJ,Kim KE,Lee HS,Oh N,Park I,Ko E,Oh SJ,Kim HC,Kim SKim SH,Kim C,Nakaoka Y,He Y,Augustin HG,Hu J,Song PH,Kim YI,Kim P,Kim I,Koh GY.
-
Journal Title
Science Translation Medicine
Volume: 8
Issue: 335
Pages: 335-355
DOI
Related Report
Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
-
[Journal Article] Gab1 adaptor protein acts as a gatekeeper to balance hepatocyte death and proliferation during acetaminophen-induced liver injury in mice.2016
Author(s)
Furuta K, Yoshida Y, Ogura S, Kurahashi T, Kizu T, Maeda S, Egawa M, Chatani N, Nishida K, Nakaoka Y, Kiso S, Kamada Y, Takehara T.
-
Journal Title
Hepatology
Volume: 63
Issue: 4
Pages: 1340-1355
DOI
Related Report
Peer Reviewed / Acknowledgement Compliant
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-