The roles of class III PI3K in cardiomyocytes

• Project/Area Number: 24790734
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Circulatory organs internal medicine
• Research Institution: Akita University
• Principal Investigator: KIMURA Hirotaka 秋田大学, 医学(系)研究科(研究院), 非常勤講師 (30382899)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2013: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: PIK3C3 / 心肥大 / 心不全 / 心筋症 / ユビキチン化 / Vps34 / Pik3c3

Research Abstract

We generated cardiomyocyte-specific Pik3c3 knockout (Pik3c3 KO) mice. Pik3c3 KO mice spontaneously developed severe cardiac hypertrophy, dysfunction of contractility, ventricular arrhythmias and sudden death. In Pik3c3 KO hearts, levels of phosphatidylinositol 3-phosphate (PI3P) were reduced. Electronmicroscopic analysis demonstrated that autophagosome was accumulated. Isolated cardiomyocytes were hypertrophic and protein aggregates were deposited in myocardium in the absence of Pik3c3 while proteasome function was normal. This aggregate included proteins degraded via vesicular trafficking, suggesting that Pik3c3 might regulate transport of polyubiquitinated proteins in vesicular trafficking. Similar protein deposition was detected in human cardiac specimen from cases with a heart disease. These findings implied that PIK3C3 deficiency might cause cardiac hypertrophy and heart failure in human.

Research Products

• [Journal Article] Deletion of autophagy-related 5 (Atg5) and Pik3c3 genes in the lens causes cataract independent of programmed organelle degradation. (2013)
  • Author(s): 森下英晃、江口賢史、木村洋貴、佐々木純子、酒巻有里子、Robinson ML、佐々木雄彦、水島昇
  • Journal Title: J Biol Chem. Volume: 288 Issue: 16 Pages: 11436-47
  • DOI: 10.1074/jbc.m112.437103
  • Peer Reviewed
• [Journal Article] Critical roles of type III phosphatidylinositol phosphate kinase in murine embryonic visceral endoderm and adult intestine (2012)
  • Author(s): Takasuga , Wada et al.
  • Journal Title: PNAS 110 Volume: 1726-1731 Issue: 5 Pages: 1726-31
  • DOI: 10.1073/pnas.1213212110
  • Peer Reviewed
• [Presentation] 心筋でのホスホイノシタイド代謝酵素Vps34の機能解析 (2013)
  • Author(s): 木村洋貴,江口賢史,久場敬司,今井由美子,小藤智史,高須賀俊輔,浅沼研,伊藤玲悦,中村亮太郎,鮎川友紀,佐々木純子,山﨑正和,佐々木雄彦
  • Organizer: 第36回日本分子生物学会
  • Place of Presentation: 神戸国際展示場
  • Year and Date: 2013-12-04
• [Presentation] 心筋でのホスホイノシタイド代謝酵素の機能解析 (2013)
  • Author(s): 木村洋貴,江口賢史,久場敬司,小藤智史,高須賀俊輔,中村亮太郎,浅沼研,鮎川友紀,佐々木純子,山﨑正和,佐々木雄彦
  • Organizer: 第2回生体情報研究シンポジウム
  • Place of Presentation: 群馬大学生体情報研究所
  • Year and Date: 2013-06-14
• [Presentation] 心筋でのホスホイノシタイド代謝酵素の機能解析 (2013)
  • Author(s): 木村洋貴，江口賢史，久場敬司，小藤智史，高須賀俊輔，中村亮太郎，浅沼研，鮎川友紀，佐々木純子，山﨑正和，佐々木雄彦
  • Organizer: 第2回生体情報研究シンポジウム
  • Place of Presentation: 群馬大学 生体調節研究所
• [Presentation] 脂質キナーゼPIK3C3欠損による自己免疫疾患 (2013)
  • Author(s): 江口賢史，木村洋貴，浅沼研，堀江泰夫，佐々木純子，佐々木雄彦
  • Organizer: 第11回北東北血液研究会
  • Place of Presentation: 秋田市
• [Book] 最新生理活性脂質研究とその臨床・創薬応用研究（仮題） 遺伝子医学 MOOK 24号 (2013)
  • Author(s): 木村洋貴，小藤智史，佐々木雄彦
  • Publisher: メディカル ドゥ