Mechanism of PACAP-induced tear secretion

• Project/Area Number: 22791695
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Ophthalmology
• Research Institution: Showa University
• Principal Investigator: NAKAMACHI Tomoya 昭和大学, 遺伝子組換え実験室, 助教 (30433840)
• Co-Investigator(Renkei-kenkyūsha): SEKI Tamotsu 昭和大学, 医学部, 兼任講師 (10245855) ; SHIODA Seiji 昭和大学, 医学部, 教授 (80102375)
• Project Period (FY): 2010 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2011: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2010: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 眼薬理学 / ドライアイ / 涙腺 / PACAP / 涙液分泌 / マウス

Research Abstract

The dry eye syndrome is one of the most common eye ailments caused by volume reduction or the altered quality of tears, however, an effective treatment has yet to be established. Our study was started based on the finding of a new phenotype in PACAP null mice, which show dry eye-like symptoms, corneal keratinization and tear reduction. PACAP and its receptor were expressed in mouse lacrimal glands, and PACAP eye drops stimulated tear secretion via an adenylate cyclase/cAMP/PKA cascade. PACAP stimulated aquaporin 5 translocation from the cytosol to the membrane in lacrimal acinar cells to induce tear secretion. These results suggest a possible role of PACAP as an endogenous regulator of tear secretion, and PACAP is a good candidate for an eye-drop medicine for the dry eye syndrome.

Research Products

• [Journal Article] Role of PACAP in Neural Stem/Progenitor Cell and Astrocyte-From Neural Development to Neural Repair (2011)
  • Author(s): Nakamachi T, Farkas J, Watanabe J, Ohtaki H, Dohi K, Arata S, Shioda S
  • Journal Title: Curr Pharm Des Volume: 17(10) Pages: 973-84
• [Journal Article] Pituitary adenylate cyclase-activating polypeptide(PACAP) stimulates proliferation of reactive astrocytes in vitro (2011)
  • Author(s): Nakamachi T, Nakamura K, Oshida K, Kagami N, Mori H, Watanabe J, Arata S, Yofu S, Endo K, Wada Y, Hori M, Tsuchikawa D, Kato M, Shioda S
  • Journal Title: J Mol Neurosci Volume: 43(1) Pages: 16-21
• [Journal Article] Suppression of rat retinal ganglion cell death by PACAP following transient ischemia induced by high intraocular pressure (2011)
  • Author(s): Seki T, Itoh H, Nakamachi T, Endo K, Wada Y, Nakamura K, Shioda S
  • Journal Title: J Mol Neurosci Volume: 43(1) Pages: 30-34
• [Journal Article] Neuroprotective effect of PACAP against NMDA-induced retinal damage in the mouse (2011)
  • Author(s): Endo K, Nakamachi T, Seki T, Kagami N, Wada Y, Nakamura K, Kishimoto K, Hori M, Tsuchikawa D, Shinntani N, Hashimoto H, Baba A, Koide R, Shioda S
  • Journal Title: J Mol Neurosci Volume: 43(1) Pages: 22-29
• [Journal Article] Pituitary adenylate cyclase-activating polypeptide (PACAP) stimulates proliferation of reactive astrocytes in vitro (2011)
  • Author(s): Nakamachi T, Nakamura K, Oshida K, Kagami N, Mori H, Watanabe J, Arata S, Yofu S, Endo K, Wada Y, Hori M, Tsuchikawa D, Kato M, Shioda S
  • Journal Title: J Mol Neurosci Volume: 43(1) Issue: 1 Pages: 16-21
  • DOI: 10.1007/s12031-010-9404-3
  • Peer Reviewed
• [Journal Article] Expression and localization of the orexin-1 receptor (OX1R) after traumatic brain injury in mice (2011)
  • Author(s): Mihara Y, Dohi K, Yofu S, Nakamachi T, Ohtaki H, Shioda S, Aruga T
  • Journal Title: J Mol Neurosci Volume: 43(2) Issue: 2 Pages: 162-8
  • DOI: 10.1007/s12031-010-9438-6
  • Peer Reviewed
• [Journal Article] Involvement of interleukin-1 in lipopolysaccaride-induced microglial activation and learning and memory deficits (2011)
  • Author(s): Tanaka S, Kondo H, Kanda K, Ashino T, Nakamachi T, Sekikawa K, Iwakura Y, Shioda S, Numazawa S, Yoshida T
  • Journal Title: J Neurosci Res Volume: 89 Issue: 4 Pages: 506-514
  • DOI: 10.1002/jnr.22582
  • Peer Reviewed
• [Journal Article] Pituitary adenylate cyclase-activating polypeptide (PACAP) stimulates proliferation of reactive astrocytes in vitro. (2011)
  • Author(s): Nakamachi T, Nakamura K, Oshida K, Kagami N, Mori H, Watanabe J, Arata S, Yofu S, Endo K, Wada Y, Hori M, Tsuchikawa D, Kato M, Shioda S.
  • Journal Title: J Mol Neurosci Volume: 43(1) Pages: 16-21
  • Peer Reviewed
• [Journal Article] Suppression of rat retinal ganglion cell death by PACAP following transient ischemia induced by high intraocular pressure. (2011)
  • Author(s): Seki T, Itoh H, Nakamachi T, Endo K, Wada Y, Nakamura K, Shioda S
  • Journal Title: J Mol Neurosci Volume: 43(1) Pages: 30-34
  • Peer Reviewed
• [Journal Article] Neuroprotective effect of PACAP against NMDA-induced retinal damage in the mouse. (2011)
  • Author(s): Endo K, Nakamachi T, Seki T, Kagami N, Wada Y, Nakamura K, Kishimoto K, Hori M, Tsuchikawa D, Shinntani N, Hashimoto H, Baba A, Koide R, Shioda S
  • Journal Title: J Mol Neurosci Volume: 43(1) Pages: 22-29
  • Peer Reviewed
• [Journal Article] Endogenous pituitary adenylate cyclase activating polypeptide is involved in suppression of edema in the ischemic brain (2010)
  • Author(s): Nakamachi T, Ohtaki H, Yofu S, Dohi K, Watanabe J, Mori H, Sato A, Hashimoto H, Shintani N, Baba A, Shioda S
  • Journal Title: Acta Neurochir Suppl Volume: 106 Pages: 43-6
• [Journal Article] Regulation of Oxidative Stress by Pituitary Adenylate Cyclase-Activating Polypeptide(PACAP) Mediated by PACAP Receptor (2010)
  • Author(s): Ohtaki H, Satoh A, Nakamachi T, Yofu S, Dohi K, Mori H, Ohara K, Miyamoto K, Hashimoto H, Shintani N, Baba A, Matsunaga M and Shioda S
  • Journal Title: J Mol Neurosci Volume: 42(3) Pages: 397-403
• [Journal Article] Cardioprotective Effect of Endogenous Pituitary Adenylate Cyclase-Activating Polypeptide on Doxorubicin-Induced Cardiomyopathy in Mice (2010)
  • Author(s): Mori H, Nakamachi T, Ohtaki H, Yofu S, Sato A, Endo K, Iso Y, Suzuki H, Takeyama Y, Shintani N, Hashimoto H, Baba A and Shioda S
  • Journal Title: Circ J Volume: 74(6) Pages: 1183-90
  • NAID: 10026474818
• [Journal Article] Cardioprotective effect of endogenous pituitary adenylate cyclase-activating polypeptide on Doxorubicin-induced cardiomyopathy in mice. (2010)
  • Author(s): Mori H, Nakamachi T, Ohtaki H, Yofu S, Sato A, Endo K, Iso Y, Suzuki H, Takeyama Y, Shintani N, Hashimoto H, Baba A, Shioda S
  • Journal Title: Circ J. Volume: 74(6) Pages: 1183-90
  • NAID: 10026474818
  • Peer Reviewed
• [Journal Article] Regulation of oxidative stress by pituitary adenylate cyclase-activating polypeptide (PACAP) mediated by PACAP receptor. (2010)
  • Author(s): Ohtaki H, Satoh A, Nakamachi T, Yofu S, Dohi K, Mori H, Ohara K, Miyamoto K, Hashimoto H, Shintani N, Baba A, Matsunaga M, Shioda S
  • Journal Title: J Mol Neurosci Volume: 42(3) Pages: 397-403
  • Peer Reviewed
• [Journal Article] IL-6 and PACAP receptor expression and localization after global brain ischemia in mice
  • Author(s): Nakamachi T, Tsuchida M, Kagami N, Yofu S, Wada Y, Hori M, Tsuchikawa D, Yoshikawa A, Imai N, Nakamura K, Arata S and Shioda S
  • Journal Title: J Mol Neurosci Volume: (in press)
• [Journal Article] Neuroprotective Effect of Endogenous PACAP on Spinal Cord Injury
  • Author(s): Tsuchikawa D, Nakamachi T, Tsuchida M, Wada Y, Hori M, Jozsef F, Yoshikawa A, Kagami N, Imai N, Shintani N, Hashimoto H, Atsumi T, and Shioda S
  • Journal Title: J Mol Neurosci Volume: (in press)
• [Presentation] PACAP誘導性の涙液分泌におけるアクアポリン5の役割 (2012)
  • Author(s): 中町智哉、会沢洋一、大滝博和、養父佐知子、関保、和田悦洋、荒田悟、新谷紀人、橋本均、馬場明道、塩田清二
  • Organizer: 第117回日本解剖学会総会・全国学術集会
  • Place of Presentation: 甲府
• [Presentation] The retinoprotective effect of exogenous PACAP involves a modulation of retinal microglia/macrophage (2011)
  • Author(s): Wada Y, Nakamachi T, Endo K, Seki T, Ohtaki H, Tsuchikawa D, Hori M, Farkas J, Tsuchida M, Yoshikawa A, Kagami N, Imai N, Shioda S
  • Organizer: The 10th international Symposium on VIP, PACAP and Related Peptides
  • Place of Presentation: Eilat, Israel
  • Year and Date: 2011-12-15
• [Presentation] PACAP stimulates the lacrimation via aquaporin 5 translocatoin in mouse (2011)
  • Author(s): Nakamchi T, Aizawa Y, Ohtaki H, Seki T, Wada Y, Kagami N, Arata S, Hashimoto H, Shintani N, Baba A, Farkas J, Reglodi D, Shioda S
  • Organizer: The 10th internatlonal Symposium on VIP, PACAP and Related Peptides
  • Place of Presentation: Eilat, Israel
  • Year and Date: 2011-12-14
• [Presentation] PACAP receptor expression and its function in mouse reactive astrocytes (2011)
  • Author(s): Nakamachi T, Jozsef F, Kagami N, Wada Y, Hori M, Tsuchikawa D, Tsuchida M, Yoshikawa A, Imai N, Hata A, Atrata S, Shioda S
  • Organizer: Symposium of the 20th Annual Meeting of The Israel Society for Neuroscience~Basic and Clinical Research of GPCRs~
  • Place of Presentation: Eilat, Israel
  • Year and Date: 2011-12-13
• [Presentation] The exogenous PACAP is possible modulater of the activation of retinal microglia/macrophage in the injury retina (2011)
  • Author(s): Wada Y, Nakamachi T, Endo K, Seki T, Ohtaki H, Tsuchikawa D, Hori M, Farkas J, Tsuchida M, Yoshikawa A, Kagami N, Imai N, Shioda S
  • Organizer: Symposium of the 20th Annual Meeting of The Israel Society for Neuroscience~Basic and Clinical Research of GPCRs~
  • Place of Presentation: Eilat, Israel
  • Year and Date: 2011-12-13
• [Presentation] Effect of pituitary adenylate cyclase-activating polypeptide (PACAP) on reactive astrocyte induced by brain damage in mice (2011)
  • Author(s): Nakamachi T, Nakamura K, Wada Y, Kagami N, Tsuchikawa D, Hori M, Imai N, Yoshikawa A, Seki T, Atrata S, Shioda S
  • Organizer: 41st Annual meeting Society for Neuroscience
  • Place of Presentation: Washington DC, USA
  • Year and Date: 2011-11-15
• [Presentation] Expression of pituitary adenylate cyclase-activating polypeptide (PACAP) receptor expression on reactive astrocyte after brain ischemia (2011)
  • Author(s): Nakamachi T, Ohtaki H, Dohi K, Kagami N, Shioda S
  • Organizer: The XVth International Symposium of Brain Edema and Cellular Injury (Brain Edema 2011)
  • Place of Presentation: Tokyo
  • Year and Date: 2011-10-22
• [Presentation] 神経幹細胞および神経腫瘍細胞の増殖調節に関する分子基盤 (2011)
  • Author(s): 中町智哉・塩田清二
  • Organizer: 昭和大学戦略的基盤研究事業
  • Place of Presentation: 東京(公開シンポジウム)
  • Year and Date: 2011-07-16
• [Presentation] PACAP遺伝子欠損マウスにおける呼吸機能異常 (2011)
  • Author(s): 中町智哉、荒田悟、鬼丸洋、塩田清二
  • Organizer: 第88回日本生理学会大会 第116回日本解剖学会総会・全国学術集会 合同大会
  • Place of Presentation: 横浜(紙面発表)
  • Year and Date: 2011-03-28
• [Presentation] PACAP receptor expression and its function in mouse reactive astrocytes (2011)
  • Author(s): Tomoya Nakamachi, Farkas Jozsef, Nobuyuki Kagami, Yoshihiro Wada, Motohide Hori, Daisuke Tsuchikawa, Masashi Tsuchida, Akira Yoshikawa, Nori Imai, Azusa Hata, Satoru Atrata, and Seiji Shioda
  • Organizer: GPCR satellite symposium
  • Place of Presentation: Eilat, Israel
• [Presentation] PACAP STIMULATES THE LACRIMATION VIA AQUAPORIN 5 TRANSLOCATOIN IN MOUSE (2011)
  • Author(s): Nakamachi T, Aizawa Y, Ohtaki H, Seki T, Wada Y, Kagami N, Arata S, Hashimoto H, Shintani N, Baba A, Farkas J, Reglodi D and Shioda S
  • Organizer: The 10th international Symposium on VIP, PACAP and Related Peptides
  • Place of Presentation: Eilat, Israel
• [Presentation] Effect of pituitary adenylate cyclase-activating polypeptide(PACAP) on reactive astrocyte induced by brain damage in mice (2011)
  • Author(s): Tomoya Nakamachi, Keisuke Nakamura, Yoshihiro Wada, Nobuyuki Kagami, Daisuke Tsuchikawa, Motohide Hori, Nori Imai, Akira Yoshikawa, Tamotsu Seki, Satoru Arata, and Seiji Shioda
  • Organizer: The 41th Annual Meeting of the Society for Neuroscience
  • Place of Presentation: Washington, DC
• [Presentation] PACAPによる涙液分泌促進作用機序の解析 (2011)
  • Author(s): 中町智哉・会沢洋一・大滝博和・関保・和田悦洋・加賀美信幸・荒田悟・塩田清二
  • Organizer: 第36回日本比較内分泌学会
  • Place of Presentation: 東京
• [Presentation] Expression of pituitary adenylate cyclase-activating polypeptide(PACAP) receptor expression on reactive astrocyte after brain ischemia in mice (2011)
  • Author(s): Tomoya Nakamachi, Hirokazu Ohtaki, Kenji Dohi, Nobuyuki Kagami, Satoru Arata and Seiji Shioda
  • Organizer: The XVth International Symposium of Brain Edema and Cellular Injury(Brain Edema 2011)
  • Place of Presentation: Tokyo
• [Presentation] 涙液分泌機能低下を示すPACAP欠損マウスを用いた涙液分泌機構の解析 (2011)
  • Author(s): 中町智哉、会沢洋一、大滝博和、関保、和田悦洋、加賀美信幸、荒田悟、塩田清二
  • Organizer: 第58回日本実験動物学会
  • Place of Presentation: 東京
• [Presentation] Investigation Of Neuroprotective Effects Of PACAP Against NMDA-induced Retinal Damage in Mice (2011)
  • Author(s): Seki T, Nakamachi T, Endo K, Shioda S
  • Organizer: ARVO(The Association for Research in Vision and Ophthalmology)
  • Place of Presentation: Fortlauderdale, Fl.
• [Presentation] PACAP遺伝子欠損マウスにおける呼吸機能異常 (2011)
  • Author(s): 中町智哉・荒田悟・鬼丸洋・塩田清二
  • Organizer: 第88回日本生理学会大会・第116回日本解剖学会総会・全国学術集会合同大会
  • Place of Presentation: 横浜
• [Presentation] Retinal Protective Effect of Pituitary Adenylate Cyclase-activating Polypeptide (PACAP) Against NMDA-induced Damage in Mice (2010)
  • Author(s): Tomoya Nakamachi, Kimi Endo, Tamotsu Seki, Nobuyuki Kagami, Keisuke Nakamura, Yoshihiro Wada, Kouji Kishimoto, Jozsef Farkas, Satoru Arata, Seiji Shioda
  • Organizer: 5th International Peptide Symposium
  • Place of Presentation: 京都
  • Year and Date: 2010-12-05
• [Presentation] Distribution of activity-dependent neuroprotective protein (ADNP) and PAC1 receptor in intact and ischemic mouse brain (2010)
  • Author(s): Tomoya Nakamachi, Kimi Endo, Tamotsu Seki, Nobuyuki Kagami, Keisuke Nakamura, Yoshihiro Wada, Kouji Kishimoto, Jozsef Farkas, Satoru Arata, Seiji Shioda
  • Organizer: 40th Annual Meeting of the Society for Neuroscience
  • Place of Presentation: サンディエゴ(USA)
  • Year and Date: 2010-11-13
• [Presentation] Retinal Protective Effect of Pituitary Adenylate Cyclase-activating Polypeptide(PACAP) Against NMDA-induced Damage in Mice (2010)
  • Author(s): Nakamachi T, Endo K, Seki T, Kagami N, Nakamura K, Wada Y, Kishimoto K, Farkas J, Arata S, Shioda S
  • Organizer: 5th International Peptide Symposium(Kyoto
  • Place of Presentation: Kyoto
• [Presentation] マウスにおけるPACAPの涙液分泌促進効果 (2010)
  • Author(s): 中町智哉
  • Organizer: 第35回日本比較内分泌学会大会
  • Place of Presentation: 静岡
• [Presentation] Distribution of activity-dependent neuroprotective protein(ADNP) and PAC1 receptor in intact and ischemic mouse brain (2010)
  • Author(s): Nakamachi T, Kagami N, Yofu S, Endo K, Nakamura K, Wada Y, Hori M, Arata S, Shioda S
  • Organizer: The 40th Annual Meeting of the Society for Neuroscience
  • Place of Presentation: San Diego, CA
• [Presentation] Deficient of learning and memory in aged PACAP-deficient mice (2010)
  • Author(s): Shioda S, Nakamachi T, Ohtaki H, Arata S
  • Organizer: 7th Joint meeting of the European Neuropeptide Club and the Summer Neuropeptide Conference
  • Place of Presentation: Pecs, Hungary
• [Presentation] 新規ドライアイ疾患モデル動物としてのPACAP遺伝子欠損マウスの評価 (2010)
  • Author(s): 中町智哉、会沢洋一、大滝博和、関保、遠藤貴美、荒田悟、新谷紀人、橋本均、馬場明道、塩田清二
  • Organizer: 第57回日本実験動物学会
  • Place of Presentation: 京都
• [Remarks]
  • URL: http://www.showa-u.ac.jp/sch/med/major/anat-1/index.html
• [Remarks]
  • URL: http://www.showa-u.ac.jp/sch/med/major/anat-1/rsch_achievement/
• [Remarks]
  • URL: http://www10.showa-u.ac.jp/~anat-1/index.html