Role of BMPR2 mutation in Pulmonary Hypertension in Rats
Project/Area Number |
17K10140
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Research Field |
Pediatrics
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Research Institution | Mie University |
Principal Investigator |
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Co-Investigator(Kenkyū-buntansha) |
丸山 一男 三重大学, 医学系研究科, 教授 (20181828)
三谷 義英 三重大学, 医学部附属病院, 准教授 (60273380)
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Project Period (FY) |
2017-04-01 – 2020-03-31
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Project Status |
Completed (Fiscal Year 2019)
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Budget Amount *help |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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Keywords | 肺高血圧 / 動物モデル / 遺伝子変異 / 肺動脈性肺高血圧 / ゲノム編集 / ラット / ラットモデル / 遺伝子改変動物 |
Outline of Final Research Achievements |
Mutations in bone morphogenetic protein receptor type-2(BMPR2) are the main genetic risk factor for developing pulmonary arterial hypertension (PAH). Recent studies have shown that PAH patients with BMPR2 mutation present earlier with severe hemodynamic compromise and worse transplant-free survival than those without mutations. The mechanisms underlying the difference in clinical phenotype in BMPR2 mutation carriers remain unclear. We tested the hypothesis that rats with a CRISPR/Cas9-mediated monoallelic BMPR2 mutation develop more severe pulmonary hypertension (PH) leading to poor survival than those without the mutation. For the first time using CRISPR/Cas9, this study demonstrates that rats with BMPR2 mutation develop MCT-PH similarly to wildtype until day21 but had poor survival thereafter and warrants further studies into underlying mechanism directing towards precision medicine in PAH targeted therapy for patients with BMPR2 mutations.
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Academic Significance and Societal Importance of the Research Achievements |
肺動脈性高血圧は予後不良疾患であり、小児においても主な死亡の原因である。原因としてBMPR2遺伝子の変異があげられ、同遺伝子変異保有患者は、重症となるとされる。しかし、肺動脈性高血圧における、BMPR2の意義は完全には理解されておらず、BMPR2変異保有患者が、より重症のPAHに進展する機序は不明である。BMPR2変異マウスを用いた研究では、ヒトと同様の病変や進行性の病態を評価することは困難であったが、最近、ゲノム編集技術の開発により、BMPR2変異ラットを用いた研究が可能となり、本研究では、最新のゲノム編集技術であるCRISPR/Cas9による変異導入ラットを用いた世界初の知見を得た。
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Report
(4 results)
Research Products
(16 results)
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[Journal Article] Detection of Pediatric Pulmonary Arterial Hypertension by School Electrocardiography Mass Screening2019
Author(s)
Sawada H, Mitani Y, Nakayama T, Fukushima H, Kogaki S, Igarashi T, Ichida F, Ono Y, Nakanishi T, Doi S, Ishikawa S, Matsushima M, Yamada O, Saji T
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Journal Title
Am J Respir Crit Care Med
Volume: 199
Pages: 1397-1406
Related Report
Peer Reviewed
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[Journal Article] Emergence and Characterization of Acute Coronary Syndrome in Adults After Confirmed or Missed History of Kawasaki Disease in Japan: A Japanese Nationwide Survey.2019
Author(s)
Mitani Y, Tsuda E, Kato H, Higaki T, Fujiwara M, Ogawa S, Satoh F, Nakamura Y, Takahashi K, Ayusawa M,Kobayashi T, Ichida F, Matsushima M, Kamada M, Suda K,Ohashi H, Sawada H, Komatsu T, Waki K, Shinoda M, Tsunoda R, Yokoi H, Hamaoka K.
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Journal Title
Front Pediatr.
Volume: 7
Pages: 275-275
Related Report
Peer Reviewed
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[Journal Article] The ALK-1/SMAD/ATOH8 axis protects against hypoxia and development of pulmonary arterial hypertension2019
Author(s)
Morikawa M, Mitani Y, Holmborn K, Kato T, Koinuma D, Maruyama J, Vasilaki E, Sawada H, Kobayashi M, Ozawa T, Morishita T, Bessho Y, Maeda S, Ledin J, Aburatani H, Kageyama R, Maruyama K, Heldin C-H, and Miyazono K.
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Journal Title
Science Signaling
Volume: 12
Related Report
Peer Reviewed
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[Journal Article] Guidelines for Heart Disease Screening in Schools (JCS 2016/JSPCCS 2016) ― Digest Version ―2018
Author(s)
umitomo N, Baba R, Doi S, Higaki T, Horie M, Nagashima M, Niwa K, Ogawa S, Okumura K, Tsutsui H (et al. )
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Journal Title
Circulation Journal
Volume: 82
Issue: 9
Pages: 2385-2444
DOI
NAID
ISSN
1346-9843, 1347-4820
Year and Date
2018-08-24
Related Report
Peer Reviewed / Open Access
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[Presentation] Inhaled Iloprost Added-On to Nitric Oxide Rescues a Neonate with Severe Congenital Diaphragmatic Hernia without Using Extracorporeal Membrane Oxygenation2019
Author(s)
Kitamura S, Sawada H, Mitani Y, Ohashi H, Yodoya N, Ooya K, Matsushita K, Koike Y, Otake K, Inoue M, Uchida K, Maruyama K and Hirayama M
Organizer
American Thoracic Society International Conference
Related Report
Int'l Joint Research
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[Presentation] Quantitative Analysis of Chest X-Ray Using Deep Learning to Predict Pulmonary to Systemic Flow Ratio in Patients With Congenital Heart Disease2019
Author(s)
Shuhei Toba,Yoshihide Mitani,Hiroyuki Ohashi,Hirofumi Sawada,Noriko Yodoya,Hidetoshi Hayakawa,Masahiro Hirayama,Ayano Futsuki,Naok iYamamoto,Hisato Ito,Takeshi Konuma,Hideto Shimpo,Motoshi Takao
Organizer
American Heart Association
Related Report
Int'l Joint Research
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