ＰＩＰ２による輸送体活性制御とその破綻による心不全機序の統合的解明

• Project Area: Establishment of Integrative Multi-level Systems Biology and its Applications
• Project/Area Number: 23136517
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Complex systems
• Research Institution: Fukuoka University
• Principal Investigator: 喜多 紗斗美 福岡大学, 医学部, 講師 (10461500)
• Project Period (FY): 2011-04-01 – 2013-03-31
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥6,760,000 (Direct Cost: ¥5,200,000、Indirect Cost: ¥1,560,000); Fiscal Year 2012: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2011: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
• Keywords: 脂質キナーゼ / 心不全 / イオン輸送

Outline of Annual Research Achievements

本研究では、種々のPIP5Kα遺伝子改変マウスをPI(4,5)P2産生量の異なるマウスとして開発・応用することにより、PI(4,5)P2によって活性制御を受けるイオン輸送体・チャネルの活性制御機構と心臓の興奮収縮連関について総合的に理解し、その破綻によって導かれる心不全の機序について検討することを目指す。平成24年度は、各種 PIP5K#61537;遺伝子改変マウス(PIP5Kα-DN-Tg、PIP5Kα-KO)を用いて、圧負荷心肥大モデルを作製し、心肥大形成および心機能について引き続き検討を行った。圧負荷心肥大モデルとして、心重量/体重比（HW/BW, mg/g）が5～6の軽度～中程度モデルと、HW/BW=6以上の重度モデルの2種類を作製した。軽度～中程度モデルの場合には野生型に比べてPIP5Kα-DN-TgおよびPIP5Kα-KOでは心肥大形成が抑制され、心機能の低下も改善された。一方、重度モデルでは、野生型、PIP5Kα-DN-TgおよびPIP5Kα-KOにおいて同程度の心肥大の形成ならびに心機能（EFおよびFS）低下の悪化が認められた。これらの結果より、心肥大の程度によってPI(4,5)P2の関与が異なる可能性が示された。また、野生型マウスの圧負荷心肥大モデルの心筋ではNCX1の膜発現が低下していた。さらに、PIP5Kα-KOの心筋細胞では野生型マウスに比べてNCX1の細胞膜での発現が低下していることから、PIP5Kα欠損によるPI(4,5)P2産生低下が引き起こすNCX1の発現異常が、心不全の発症に関与する可能性が示唆された。

Research Progress Status

24年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

24年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Na+/Ca2+ exchanger 2-heterozygote knockout mice display decreased acetylcholine release and altered colonic motility in vivo. (2012)
  • Author(s): Azuma YT, Nishiyama K, Kita S, Komuro I, Nakajima H, Iwamoto T, Takeuchi T
  • Journal Title: Neurogastroenterol Motil Volume: 24(12) Issue: 12
  • DOI: 10.1111/nmo.12029
  • Peer Reviewed
• [Journal Article] Preferential involvement of Na+/Ca2+ exchanger type-1 in the brain damage caused by transient focal cerebral ischemia in mice. (2012)
  • Author(s): Morimoto N, Kita S, Shimazawa M, Namimatsu H, Tsuruma K, Hayakawa K, Mishima K, Egashira N, Iyoda T, Horie I, Gotoh Y, Iwasaki K, Fujiwara M, Matsuda T, Baba A, Komuro I, Horie K, Takeda J, Iwamoto T, Hara H.
  • Journal Title: Biochem Biophys Res Commun Volume: 429(3-4) Issue: 3-4 Pages: 186-190
  • DOI: 10.1016/j.bbrc.2012.10.114
  • Peer Reviewed
• [Journal Article] Functional interaction between Na+/Ca2+ exchanger and sodium-transporting proteins in plasma membrane microdomains. (2012)
  • Author(s): Kita, S.
  • Journal Title: Nihon Yakurigaku Zasshi Volume: 139 Pages: 61-65
  • NAID: 10030456141
• [Journal Article] Effect of heterozygous deletion of WNK1 on the WNK-OSR1/SPAK-NCC/NKCC1/NKCC2 signal cascade in the kidney and blood bessels (2012)
  • Author(s): Susa, K.
  • Journal Title: Clin Exp Nephrol Volume: (in press)
  • Peer Reviewed
• [Journal Article] Functional interaction between Na^+/Ca^<2+> exchanger and sodium-transporting protein in plasma membrane microdomains (2012)
  • Author(s): Kita, S.
  • Journal Title: Nihon Yakurigaku Zasshi Volume: 139 Pages: 61-65
  • NAID: 10030456141
  • Peer Reviewed
• [Journal Article] TRIC-A channels in vascular smooth muscle contribute to blood pressure maintenance (2011)
  • Author(s): Yamazaki, D.
  • Journal Title: Cell Metab Volume: 14 Pages: 231-241
  • Peer Reviewed
• [Journal Article] New molecular mechanisms for cardiovascular disease : cardiac hypertrophy and cell-volume regulation (2011)
  • Author(s): Yamamoto, S.
  • Journal Title: J Pharmacol Sci Volume: 116 Pages: 343-349
  • Peer Reviewed
• [Journal Article] Cilostazol suppresses angiotensin II-induced vasoconstriction via protein kinase A-mediated phosphorylation of the transient receptor potential canonical 6 channel (2011)
  • Author(s): Nishioka, K.
  • Journal Title: Arterioscler Thromb Vasc Biol Volume: 31 Pages: 2278-2286
  • Peer Reviewed
• [Presentation] Involvement of PIP5-kinase in pressure overload-induced hypertrophy (2013)
  • Author(s): Kita, S.
  • Organizer: 第86回日本薬理学会年会
  • Place of Presentation: 福岡
  • Year and Date: 2013-03-21
• [Presentation] Ca2+ mobilization mechanisms through TRPCs and NCX1 in regulation of vascular tonus (2013)
  • Author(s): Kita, S.
  • Organizer: 第86回日本薬理学会年会
  • Place of Presentation: 福岡
  • Year and Date: 2013-03-21
• [Presentation] Preferential involvement of NCX1 in the brain damage caused by transient focal cerebral ischemia in mice (2013)
  • Author(s): Kita, S.
  • Organizer: Biophysical Society 57th Annual Meeting
  • Place of Presentation: Philadelphia, USA
  • Year and Date: 2013-02-02
• [Presentation] Involvement of TRPC3 and TRPC6 channels in myogenic tone regulation of murine mesenteric arteries (2012)
  • Author(s): Kita, S.
  • Organizer: 第35回日本分子生物学会大会
  • Place of Presentation: 福岡
  • Year and Date: 2012-12-11
• [Presentation] Pharmacological profile of YM-244769, a specific NCX inhibitor, in cardiac myocytes (2012)
  • Author(s): 喜多紗斗美
  • Organizer: 第85回日本薬理学会年会
  • Place of Presentation: 京都国際会館(京都)
  • Year and Date: 2012-03-14
• [Presentation] Vascular Na^+/Ca^<2+> exchanger type-1 contributes to hypertension in pseudohypoaldosteronism type II and Cushing's syndrome models (2012)
  • Author(s): Kita, S.
  • Organizer: Biophysical Society 56th Annual Meeting
  • Place of Presentation: San Diego(米国)
  • Year and Date: 2012-02-29
• [Presentation] Pharmacological properties of YM-244769, a specific Na^+/Ca^<2+> inhibitor, in cardiac myocytes (2012)
  • Author(s): Kita, S.
  • Organizer: Biophysical Society 56th Annual Meeting
  • Place of Presentation: San Diego(米国)
  • Year and Date: 2012-02-29
• [Presentation] Cardiac-specific overexpression of NCX1.1 mutant induces dilated cardiomyopathy in mice (2012)
  • Author(s): Kita, S.
  • Organizer: The 1st HD Physiology International Symposium
  • Place of Presentation: 武田先端知ビル(東京)
  • Year and Date: 2012-01-21
• [Presentation] Pharmacological profile of YM-244769, a specific NCX inhibitor, in cardiac myocytes (2012)
  • Author(s): Kita, S.
  • Organizer: The 1st HD Physiology International Symposium
  • Place of Presentation: 武田先端知ビル(東京)
  • Year and Date: 2012-01-21
• [Presentation] YM-244769, a novel specific NCX inhibitor, efficiently protects against Ca^<2+> overload-induced cardiac cell damage (2011)
  • Author(s): Iwamoto, T.
  • Organizer: 第34回日本分子生物学会大会
  • Place of Presentation: パシフィコ横浜(神奈川)
  • Year and Date: 2011-12-14
• [Book] トランスポートソームの世界 (2011)
  • Author(s): 金井好克/竹島浩/森泰生/久保義弘
  • Publisher: 京都広川書店
• [Remarks] 福岡大学医学部薬理学教室
  • URL: http://www.med.fukuoka-u.ac.jp/pharmaco/index.html
• [Remarks]
  • URL: http://www.med.fukuoka-u.ac.jp/