2014 Fiscal Year Annual Research Report
心筋細胞シグナルパスウェイ制御機構と神経性調節の統合的解明
Project Area | Establishment of Integrative Multi-level Systems Biology and its Applications |
Project/Area Number |
22136009
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Research Institution | Yokohama City University |
Principal Investigator |
石川 義弘 横浜市立大学, 医学(系)研究科(研究院), 教授 (40305470)
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Co-Investigator(Kenkyū-buntansha) |
赤羽 悟美 東邦大学, 医学部, 教授 (00184185)
奥村 敏 鶴見大学, 歯学部, 教授 (60233475)
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Project Period (FY) |
2010-04-01 – 2015-03-31
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Keywords | シグナル伝達 / 生理学 / 循環器・高血圧 |
Outline of Annual Research Achievements |
cAMPを介した自律神経シグナルは心機能を調節するだけでなく、Ca2+チャネルの活動を制御して、不整脈発生にも大きな役割を果たす。本研究では、心筋細胞における両者の破綻メカニズムを、不整脈の発生制御の観点から統合的に理解し、抗不整脈剤等の効果を含めた予測医学への発展を目指した。これまでに多階層的システムバイオロジー研究のモデルとして、Ca2+チャネルとアデニル酸シクラーゼを設定し、時間・空間的にどのような複合的な制御を受けるのかを検討した。さらに得られた遺伝子操作動物や作動薬を用いた実験結果と統合することにより、システムバイオロジー手法を用いて、Ca2+とcAMPシグナルの相互抑制作用のメカニズムを検証し、両諸条件を解明した。最終年度である平成26年度には、これまでの研究成果を統合し、cAMPを介した自律神経シグナルとCa2+チャネルの活動の制御および不整脈研究に向けて実用化に向けた検討を総括し、研究論文として発表した。 すでにCa2+流入によるアデニル酸シクラーゼの直接抑制だけでは、長期的な時間的位相差を示すオシレーションは困難であり、リン酸化や自律神経の活性化による刺激を組み入れることが、位相差の維には必要である。これらの条件をCell Designerを用いて検証し、細胞内Ca2+濃度がcAMP濃度とオシレーションする諸条件を時間的に解明した。さらに数理モデルを動物モデルで検証するために、心臓型アデニル酸シクラーゼ欠損動物でcAMPシグナルの質的な変化をもたせ、心房性を中心に不整脈の誘導性を検討した。Cell Designerとの連動性の検討によって、生体制御系の諸因子を取り込みながら、さらに同一班内の研究者と検討し、不整脈を中心とする心疾患における予測および治療標的の検討を進めることができた。
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Research Progress Status |
26年度が最終年度であるため、記入しない。
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Strategy for Future Research Activity |
26年度が最終年度であるため、記入しない。
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Research Products
(47 results)
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[Journal Article] Oscillation of cAMP and Ca2+ in cardiac myocytes.2015
Author(s)
Kamide T, Okumura S, Ghosh S, Shinoda Y, Mototani Y, Ohnuki Y, Jin H, Cai W, Suita K, Sato I, Umemura M, Fujita T, Yokoyama U, Sato M, Frutani K, Kitano H, and Ishikawa Y.
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Journal Title
J. Physiol. Sci.
Volume: 65
Pages: 195-200
DOI
Peer Reviewed
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[Journal Article] Coupling of beta1-adrenergic receptor to type 5 adenylyl cyclase and its physiological relevance in cardiac myocytes.2015
Author(s)
Tsunematsu T, Okumura S, Mototani Y, Ohnuki Y, Jin H, Cai W, SuitaK, Sato I, Umemura M, Yokoyama U, Sato M, Fujita T, and Ishikawa Y.
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Journal Title
Biochem. Biophys. Res. Commun.
Volume: 458
Pages: 531-535
DOI
Peer Reviewed
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[Journal Article] A magnetic anti-cancer compound for magnet-guided delivery and magnetic resonance imaging.2015
Author(s)
Eguchi H, Umemura M, Kurotani R, Fukumura H, Sato I, Kim J-H, Hoshino Y, Lee J, Amemiya N, Sato M, Hirata K, Sigh DJ, Masuda T, Yamamoto M, Urano T, Yoshida K, Tanigaki K, Yamamoto M, Sato M, Inoue S, Aoki I and Ishikawa Y.
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Journal Title
Sci. Rep.
Volume: 5
Pages: 9194
DOI
Peer Reviewed
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[Journal Article] Prostaglandin E2 inhibits elastogenesis in the ductus arteriosus via EP4 signaling.2014
Author(s)
Yokoyama U, Minamisawa S, Shioda A, Ishiwata R, Jin MH, Masuda M, Asou T, Sugimoto Y, Aoki H, Nakamura T, and Ishikawa Y
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Journal Title
Circulation.
Volume: 129
Pages: 487-496
DOI
Peer Reviewed
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[Journal Article] Store-operated Ca²⁺ entry (SOCE) Regulates Melanoma Proliferation and Cell Migration. Cell2014
Author(s)
Umemura M, Baljinnyam E, Feske S, De Lorenzo MS, Xie LH, Feng X, Oda K, Makino A, Fujita T, Yokoyama U, Iwatsubo M, Chen S, Goydos JS, Ishikawa Y, and Iwatsubo K
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Journal Title
PloS One.
Volume: 9
Pages: e89292
DOI
Peer Reviewed
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[Journal Article] Hyperthermia generated with ferucarbotran (Resovist®) in an alternating magnetic field enhances cisplatin-induced apoptosis of cultured human oral cancer cells.2014
Author(s)
Sato I, Umemura M, Mitsudo K, Kioi M, Nakashima H, Iwai T, Feng X, Oda K, Miyajima A, Makino A, Iwai M, Fujita T, Yokoyama U, Okumura S, Sato M, Eguchi H, Tohnai I, Ishikawa Y
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Journal Title
J Physiol Sci.
Volume: 64
Pages: 177-183
DOI
Peer Reviewed
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[Journal Article] Decreased serum osmolality promotes ductus arteriosus constriction.2014
Author(s)
Aoki R, Yokoyama U, Ichikawa Y, Taguri M, Kumagaya S, Ishiwata R, Yanai C, Fujita S, Umemura M, Fujita T, Okumura S, Sato M, Minamisawa S, Asou T, Masuda M, Iwasaki S, Nishimaki S, Seki K, Yokota S, and Ishikawa Y
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Journal Title
Cardiovasc. Res.
Volume: 104
Pages: 326-336
DOI
Peer Reviewed
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[Journal Article] Three-dimensional multilayers of smooth muscle cells as a new experimental model for vascular elastic fiber formation studies.2014
Author(s)
Ishiwata R, Yokoyama U, Matsusaki M, Asano Y, Kadowaki K, Ichikawa Y, Umemura M, Fujita T, Minamisawa S, Shimoda H, Akashi M, Ishikawa Y
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Journal Title
Atherosclerosis.
Volume: 233
Pages: 590-600
DOI
Peer Reviewed
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[Journal Article] Epac1-dependent phospholamban phosphorylation mediates the cardiac response to stresses.2014
Author(s)
Okumura S, Fujita T, Cai W, Jin M, Namekata I, Mototani Y, Jin H, Ohnuki Y, Tsuneoka Y, Kurotani R, Suita K, Kawakami Y, Hamaguchi S, Abe T, Kiyonari H, Tsunematsu T, Bai Y, Suzuki S, Hidaka Y, Umemura M, Ichikawa Y, Yokoyama U, Sato M, Ishikawa F, Izumi-Nakaseko H, Adachi-Akahane S, Tanaka H, Ishikawa Y
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Journal Title
J Clin Invest.
Volume: 124
Pages: 2785-2801
DOI
Peer Reviewed
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[Journal Article] Impaired NO Production and Increased Blood Pressure in Systemic Heterozygous ATP2B1 Null Mice.2014
Author(s)
Fujiwara A, Hirawa N, Fujita M, Kobayashi Y, Okuyama Y, Yatsu K, Katsumata M, Yamamoto y, Ichihara N, Saka S, Toya Y, Yasuda G, Tabara Y, Miki T, Ueshima H, Ishikawa Y, and Umemura S
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Journal Title
J Hypertension.
Volume: 32
Pages: 1415-1423
DOI
Peer Reviewed
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[Journal Article] Deletion of the angiotensin II type 1 receptor-associated protein enhances renal sodium reabsorption and exacerbates angiotensin II-mediated hypertension.2014
Author(s)
Ohsawa M, Tamura K, Wakui H, Maeda A, Dejima T, Kanaoka T, Azushima K, Uneda K, Tsurumi-Ikeya Y, Kobayashi R, Matsuda M, Uchida S, Toya Y, Kobori H, Nishiyama A, Yamashita A, Ishikawa Y, and Umemura S
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Journal Title
Kidney International.
Volume: 86
Pages: 570-581
DOI
Peer Reviewed
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[Journal Article] Role of Cyclic AMP Sensor Epac1 in Masseter Muscle Hypertrophy and Myosin Heavy Chain Transition Induced by 2-Adrenoceptor Stimulation.2014
Author(s)
Ohnuki Y, Umeki D, Mototani Y, Jin H, Cai W, Shiozawa K, Suita K, Saeki Y, Fujita T, Ishikawa Y, and Okumura S.
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Journal Title
J. Physiol.
Volume: 592
Pages: 5461-5475
DOI
Peer Reviewed
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[Presentation] Methotrexate derivative with intrinsic magnetism.2015
Author(s)
Umemura M, Katsumata M, Sato I, Nagasako A, Aoyama H, Makino A, Ohatake M, Oda K, Eguchi H, Ishikawa Y.
Organizer
The 106th American Association for Cancer Research Annual meeting
Place of Presentation
Philadelphia, USA
Year and Date
2015-04-18 – 2015-04-22
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[Presentation] Simultaneous hyperthermic-chemotherapy for glioblastoma using a single anti-cancer compound with magnetism.2015
Author(s)
Ohtake M, Umemura M, Sato I, Oda K, Nagasako A, Makino A, Aoyama H, Katsumata M, Eguchi H, Kawahara N , Ishikawa Y.
Organizer
The 106th American Association for Cancer Research Annual meeting.
Place of Presentation
Philadelphia, USA
Year and Date
2015-04-18 – 2015-04-22
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[Presentation] Cardiac overexpression ofure. Chronic Treatment with Dihydroartemisinin, a TCTP Down-regulating Agent, Results in Cardiac Dysfunction in Mice.2014
Author(s)
Cai W, Fujita T, Hidaka Y, Jin H, K. Sagara S, Kubota K, Suita K, Ishikawa Y.
Organizer
European Society of Cardiorogy Congress.
Place of Presentation
Barcelona, Spain
Year and Date
2014-08-30 – 2014-09-03
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[Presentation] Vidarabine, an anti-herpesvirus agent, prevents catecholamine-induced atrial fibrillation in mice.2014
Author(s)
Sujita K, Fujita T, Cai W, Hidaka Y, Jin H, Jin M, Okumura S, Ishikawa Y.
Organizer
European Society of Cardiorogy Congress.
Place of Presentation
Barcelona, Spain
Year and Date
2014-08-30 – 2014-09-03
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[Presentation] A novel treatment for triple-negative breast cancer using intrinsic magnetized paclitaxel.2014
Author(s)
Umemura M, Makino A, Sato I, Feng X, Iwai M, Oda K, Miyajima A, Otake M, Nagasako A, Matsuo K, Eguchi H, and Ishikawa Y.
Organizer
The 105th American Association for Cancer Research Annual meeting.
Place of Presentation
San Diego, USA
Year and Date
2014-04-05 – 2014-04-09
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