Basic research of prevention and intervention for congenital cardiac outflow tract defects using animal models

• Project/Area Number: 25293238
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Keio University
• Principal Investigator: Yamagishi Hiroyuki 慶應義塾大学, 医学部, 准教授 (40255500)
• Co-Investigator(Kenkyū-buntansha): TSUCHIHASHI TAKATOSHI 慶應義塾大学, 医学部, 共同研究員 (10286528) ; MAKINO SHINJI 慶應義塾大学, 医学部, 准教授 (20306707) ; UCHIDA KEIKO 慶應義塾大学, 保健管理センター, 講師 (50286522) ; YUASA SHINSUKE 慶應義塾大学, 医学部, 准教授 (90398628)
• Co-Investigator(Renkei-kenkyūsha): IEDA MASAKI 慶應義塾大学, 医学部, 講師 (70296557)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥18,460,000 (Direct Cost: ¥14,200,000、Indirect Cost: ¥4,260,000); Fiscal Year 2015: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2013: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000)
• Keywords: 発生・分化 / 発現制御 / 遺伝子 / 循環器・高血圧 / 再生医学 / 発生分化

Outline of Final Research Achievements

Using the murine model, we identified that the expression of a neurovascular guiding molecule, Sema3C, is regulated positively by Foxc1 and Foxc2, and negatively by Tbx1 directly in the second heart field and through Fgf8 which is a downstream effector of Tbx1 in the neural crest, respectively, during development of the cardiac outflow tract. Such dynamic temporo-spatial regulation of Sema3c plays a role in the fine tuning of migration of neural crest cells into the outflow tract to give rise to the septum. We also succeeded in visualization of the development of pulmonary arteries from central to peripheral regions of the lungs using a transgenic mouse model in which the lacZ marker gene was inserted into the genome of IP3R type2. Using this mouse model, we also showed the mechanism of pulmonary vascular abnormality associated with cardiac outflow tract defects and candidates of unknown cis/trans elements that specifically regulate the development of pulmonary arterial smooth muscle.

Research Products

• [Journal Article] Variable severity of cardiovascular phenotypes in patients with an early‑onset form of Marfan syndrome harboring FBN1 mutations in exons 24–32 (2016)
  • Author(s): Maeda J, Kosaki K, Shiono J, Kouno K, Aeba R, Yamagishi H
  • Journal Title: Heart Vessels Volume: online 21 Jan Issue: 10 Pages: 1-7
  • DOI: 10.1007/s00380-016-0793-2
  • Peer Reviewed / Open Access
• [Journal Article] Pulmonary Arterial Hypertension Associated With Tetralogy of Fallot (2015)
  • Author(s): Yasuhara J, Yamagishi H
  • Journal Title: International Heart Journal Volume: 56 Issue: Supplement Pages: S17-S21
  • DOI: 10.1536/ihj.14-351
  • NAID: 130004941325
  • ISSN: 1349-2365, 1349-3299
  • Peer Reviewed / Open Access
• [Journal Article] 【作用機序から考える薬物療法】 肺高血圧症 (2015)
  • Author(s): 小柳喬幸, 山岸敬幸
  • Journal Title: 小児科 Volume: 56 Pages: 251-259
• [Journal Article] 【小児循環器診療のいま】 ピンポイント小児医療 心筋疾患 診断 肥大型心筋症と症候群 (2015)
  • Author(s): 石崎怜奈, 山岸敬幸
  • Journal Title: 小児内科 Volume: 47 Pages: 214-219
• [Journal Article] Myocardium-derived angiopoietin-1 is essential for coronary vein formation in the developing heart (2014)
  • Author(s): Arita Y, Nakaoka Y, Matsunaga T, Kidoya H, Yamamizu K, Arima Y, Kataoka-Hashimoto T, Ikeoka K, Yasui T, Masaki T, Yamamoto K, Higuchi K, Park JS, Shirai M, Nishiyama K, Yamagishi H, Otsu K, Kurihara H, Minami T, Yamauchi-Takihara K, Koh GY, Mochizuki N, Takakura N, Sakata Y, Yamashita JK, Komuro I
  • Journal Title: Nat Commun Volume: 5 Issue: 1 Pages: 4452-4452
  • DOI: 10.1038/ncomms5552
  • Peer Reviewed / Open Access
• [Journal Article] Acute rupture of chordae tendineae of the mitral valve in infants: a nationwide survey in Japan exploring a new syndrome. (2014)
  • Author(s): Shiraishi I, Nishimura K, Sakaguchi H, Abe T, Kitano M, Kurosaki K, Kato H, Nakanishi T, Yamagishi H, Sagawa K, Ikeda Y, Morisaki T, Hoashi T, Kagisaki K, Ichikawa H.
  • Journal Title: Circulation Volume: 130 Issue: 13 Pages: 1053-1061
  • DOI: 10.1161/circulationaha.114.008592
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] MiR-133 promotes cardiac reprogramming by directly repressing Snai1 and silencing fibroblast signatures. (2014)
  • Author(s): Mizuha Akiyama, Rie Wada, Kohei Inagawa, Takahiko Nishiyama, Ruri Kaneda, Toru Fukuda, Shu Takeda, Shugo Tohyama, Hisayuki Hashimoto, Yoshifumi Kawamura, Naoki Goshima, Ryo Aeba, Hiroyuki Yamagishi, Keiichi Fukuda, Masaki Ieda
  • Journal Title: EMBO J. Volume: 33 Issue: 14 Pages: 1565-1581
  • DOI: 10.15252/embj.201387605
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Induction of human cardiomyocyte-like cells from fibroblasts by defined factors (2013)
  • Author(s): Wada R, Muraoka N, Inagawa K, Yamakawa H, Miyamoto K, Sadahiro T, Umei T, Kaneda R, Suzuki T, Kamiya K, Tohyama S, Yuasa S, Kokaji K, Aeba R, Yozu R, Yamagishi H, Kitamura T, Fukuda K, Ieda M
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 110 Pages: 12667-12672
  • Peer Reviewed
• [Presentation] 先天性心疾患の診療をもっと面白くする臨床心臓発生学のすゝめ (2015)
  • Author(s): 山岸敬幸
  • Organizer: 第33回中国四国地区小児循環器懇話会
  • Place of Presentation: 岡山国際交流センター（岡山県岡山市）
  • Year and Date: 2015-09-05
  • Invited
• [Presentation] A history and interaction of outflow progenitor cells implicated in TAKAO syndrome. (2013)
  • Author(s): Hiroyuki Yamagishi
  • Organizer: The 7th TAKAO International Symposium on Etiology and Morphogenesis of Congenital Heart Disease
  • Place of Presentation: Tokyo
  • Invited
• [Presentation] Understanding the developing mechanism of Truncus Arteriosus by Tbx1 hypomorphic mouse. (2013)
  • Author(s): Understanding the developing mechanism of Truncus Arteriosus by Tbx1 hypomorphic mouse. Takatoshi Tsuchihashi, Reina Ishizaki, Akimichi Shibata, Keiko Uchida, Hiroyuki Yamagishi
  • Organizer: The 7th TAKAO International Symposium on Etiology and Morphogenesis of Congenital Heart Disease
  • Place of Presentation: Tokyo
• [Book] Congenital Heart Disease The Broken Heart (2016)
  • Author(s): Yamagishi H
  • Total Pages: 765
  • Publisher: Springer
• [Book] Etiology and Morphogenesis of Congenital Heart Disease (2016)
  • Author(s): Yamagishi H, Kodo K, Maeda J, Uchida K, Tsuchihashi T, Shibata A, Ishizaki R, Yamagishi C, Srivastava D
  • Total Pages: 383
  • Publisher: Springer
• [Book] Cardiac Regeneration Using Stem Cells (2013)
  • Author(s): Hiroyuki Yamagishi
  • Total Pages: 366
  • Publisher: CRC Press
• [Book] Cardiac CT and MR for Adult Congenital Heart Disease (2013)
  • Author(s): Hiroyuki Yamagishi, Chihiro Yamagishi
  • Total Pages: 733
  • Publisher: Springer