Elucidation of the mechanism for acivity regulation of HDL-interacting proteins

• Project/Area Number: 16K08236
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Biological pharmacy
• Research Institution: The University of Tokushima
• Principal Investigator: OKUHIRA Keiichiro 徳島大学, 大学院医歯薬学研究部(薬学域), 准教授 (10425671)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2019: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 脂質 / 動脈硬化 / リポタンパク質 / HDL

Outline of Final Research Achievements

Elevated levels of high-density lipoprotein cholesterol (HDL-C) reduce the risk of coronary artery disease. HDL is known to exhibit anti-atherogenic effects by multiple mechanisms such as cholesterol efflux from atherosclerotic plaque, anti-inflammatory, and antioxidant effects. Here we showed that apoA-I binding protein (AIBP), which potentially interact with HDL in plasma, exert an anti-atherosclerotic effects by enhancing the HDL ability of promoting lipid efflux and anti-inflammation. Our findings uncovered a novel role of AIBP in atherosclerosis.

Academic Significance and Societal Importance of the Research Achievements

HDLが上昇することで、形成された病変が縮小する動脈硬化の治療効果が期待できることから、HDL創薬の社会的・医療経済的意義は大きい。本研究によって得られた知見は、これまでほとんど機能未知だったAIBPの生理的な作用について明らかにしており、学術的意義のみならず、HDL創薬への新しい可能性を示したという点で、それに応えるものである。

Research Products

• [Int'l Joint Research] Massachusetts General Hospital(米国)
• [Journal Article] A Photo-Activatable Peptide Mimicking Functions of Apolipoprotein A-I (2019)
  • Author(s): Haruka Kawahara, Naoki Miyashita, Kohki Tachibana, Yusuke Tsuda, Kyohei Morimoto, Kouhei Tsuji, Akira Shigenaga, Akira Otaka, Tatsuhiro Ishida and Keiichiro Okuhira
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 42 Issue: 6 Pages: 1019-1024
  • DOI: 10.1248/bpb.b19-00114
  • NAID: 130007657697
  • ISSN: 0918-6158, 1347-5215
  • Year and Date: 2019-06-01
  • Peer Reviewed / Open Access
• [Journal Article] A simplified method for manufacturing RNAi therapeutics for local administration (2019)
  • Author(s): Ando Hidenori、Abu Lila Amr S.、Fukushima Masakazu、Matsuoka Rie、Shimizu Taro、Okuhira Keiichiro、Ishima Yu、Huang Cheng-Long、Wada Hiromi、Ishida Tatsuhiro
  • Journal Title: International Journal of Pharmaceutics Volume: 564 Pages: 256-262
  • DOI: 10.1016/j.ijpharm.2019.04.054
  • Peer Reviewed
• [Journal Article] Distribution of Polysulfide in Human Biological Fluids and Their Association with Amylase and Sperm Activities (2019)
  • Author(s): Ikeda Mayumi、Ishima Yu、Chuang Victor T. G.、Sakai Maki、Osafune Hiroki、Ando Hidenori、Shimizu Taro、Okuhira Keiichiro、Watanabe Hiroshi、Maruyama Toru、Otagiri Masaki、Akaike Takaaki、Ishida Tatsuhiro
  • Journal Title: Molecules Volume: 24 Issue: 9 Pages: 1689-1689
  • DOI: 10.3390/molecules24091689
  • NAID: 120006995454
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cancer cell-type tropism is one of crucial determinants for the efficient systemic delivery of cancer cell-derived exosomes to tumor tissues (2019)
  • Author(s): Emam Sherif E.、Abu Lila Amr Selim、Elsadek Nehal E.、Ando Hidenori、Shimizu Taro、Okuhira Keiichiro、Ishima Yu、Mahdy Mahmoud A.、Ghazy Fakhr-eldin S.、Ishida Tatsuhiro
  • Journal Title: European Journal of Pharmaceutics and Biopharmaceutics Volume: 145 Pages: 27-34
  • DOI: 10.1016/j.ejpb.2019.10.005
  • Peer Reviewed
• [Journal Article] Albumin domain mutants with enhanced Aβ binding capacity identified by phage display analysis for application in various peripheral Aβ elimination approaches of Alzheimer's disease treatment (2019)
  • Author(s): Ishima Yu、Mimono Ai、Tuan Giam Chuang Victor、Fukuda Tetsuya、Kusumoto Kohshi、Okuhira Keiichiro、Suwa Yoshiaki、Watanabe Hiroshi、Ishida Tatsuhiro、Morioka Hiroshi、Maruyama Toru、Otagiri Masaki
  • Journal Title: IUBMB Life Volume: 72 Issue: 4 Pages: 641-651
  • DOI: 10.1002/iub.2203
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Doxorubicin Expands <i>in Vivo</i> Secretion of Circulating Exosome in Mice (2018)
  • Author(s): Emam Sherif E.、Ando Hidenori、Abu Lila Amr Selim、Kobayashi Shinya、Shimizu Taro、Okuhira Keiichiro、Ishima Yu、Ishida Tatsuhiro
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 41 Issue: 7 Pages: 1078-1083
  • DOI: 10.1248/bpb.b18-00202
  • NAID: 130007387206
  • ISSN: 0918-6158, 1347-5215
  • Year and Date: 2018-07-01
  • Peer Reviewed
• [Journal Article] A Novel Strategy to Increase the Yield of Exosomes (Extracellular Vesicles) for an Expansion of Basic Research (2018)
  • Author(s): Emam Sherif E.、Ando Hidenori、Abu Lila Amr Selim、Shimizu Taro、Ukawa Masami、Okuhira Keiichiro、Ishima Yu、Mahdy Mahmoud A.、Ghazy Fakhr-eldin S.、Ishida Tatsuhiro
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 41 Issue: 5 Pages: 733-742
  • DOI: 10.1248/bpb.b17-00919
  • NAID: 130006730692
  • ISSN: 0918-6158, 1347-5215
  • Year and Date: 2018-05-01
  • Peer Reviewed
• [Journal Article] Reactivity of IgM antibodies elicited by PEGylated liposomes or PEGylated lipoplexes against auto and foreign antigens. (2018)
  • Author(s): 8.Ando, H., Abu Lila, A.S., Kawanishi, M., Shimizu, T., Okuhira, K., Ishima, Y., Ishida, T.
  • Journal Title: J. Control Release Volume: 270 Pages: 114-119
  • DOI: 10.1016/j.jconrel.2017.12.002
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Intratumoral visualization of oxaliplatin within a liposomal formulation using X-ray fluorescence spectrometry. (2018)
  • Author(s): 5.Ando, H., Abu Lila, A.S., Tanaka, M., Doi, Y., Terada, Y., Yagi, N., Shimizu, T., Okuhira, K., Ishima, Y., Ishida, T.,
  • Journal Title: Mol Pharm. Volume: 15 Issue: 2 Pages: 403-409
  • DOI: 10.1021/acs.molpharmaceut.7b00762
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A hydroxyl PEG version of PEGylated liposomes and its impact on anti-PEG IgM induction and on the accelerated clearance of PEGylated liposomes (2018)
  • Author(s): Shimizu Taro、Abu Lila Amr S.、Fujita Risako、Awata Mizuki、Kawanishi Munehira、Hashimoto Yosuke、Okuhira Keiichiro、Ishima Yu、Ishida Tatsuhiro
  • Journal Title: European Journal of Pharmaceutics and Biopharmaceutics Volume: 127 Pages: 142-149
  • DOI: 10.1016/j.ejpb.2018.02.019
  • Peer Reviewed
• [Journal Article] Derivatization of inhibitor of apoptosis protein (IAP) ligands yields improved inducers of estrogen receptor α degradation (2018)
  • Author(s): Ohoka Nobumichi、Morita Yoko、Nagai Katsunori、Shimokawa Kenichiro、Ujikawa Osamu、Fujimori Ikuo、Ito Masahiro、Hayase Youji、Okuhira Keiichiro、Shibata Norihito、Hattori Takayuki、Sameshima Tomoya、Sano Osamu、Koyama Ryokichi、Imaeda Yasuhiro、Nara Hiroshi、Cho Nobuo、Naito Mikihiko
  • Journal Title: Journal of Biological Chemistry Volume: 293 Issue: 18 Pages: 6776-6790
  • DOI: 10.1074/jbc.ra117.001091
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Effect of Phosphatidylserine and Cholesterol on Membrane-mediated Fibril Formation by the N-terminal Amyloidogenic Fragment of Apolipoprotein A-I (2018)
  • Author(s): Mizuguchi Chiharu、Nakamura Mitsuki、Kurimitsu Naoko、Ohgita Takashi、Nishitsuji Kazuchika、Baba Teruhiko、Shigenaga Akira、Shimanouchi Toshinori、Okuhira Keiichiro、Otaka Akira、Saito Hiroyuki
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 5497-5497
  • DOI: 10.1038/s41598-018-23920-3
  • Peer Reviewed / Open Access
• [Journal Article] Liposome co-incubation with cancer cells secreted exosomes (extracellular vesicles) with different proteins expressions and different uptake pathways (2018)
  • Author(s): Emam Sherif E.、Ando Hidenori、Lila Amr S. Abu、Shimizu Taro、Okuhira Keiichiro、Ishima Yu、Mahdy Mahmoud A.、Ghazy Fakhr-eldin S.、Sagawa Ikuko、Ishida Tatsuhiro
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 14493-14493
  • DOI: 10.1038/s41598-018-32861-w
  • NAID: 120006875666
  • Peer Reviewed / Open Access
• [Journal Article] A Cell Assay for Detecting Anti-PEG Immune Response against PEG-Modified Therapeutics (2018)
  • Author(s): Shimizu Taro、Abu Lila Amr S.、Awata Mizuki、Kubo Yukiyo、Mima Yu、Hashimoto Yosuke、Ando Hidenori、Okuhira Keiichiro、Ishima Yu、Ishida Tatsuhiro
  • Journal Title: Pharmaceutical Research Volume: 35 Issue: 11 Pages: 223-223
  • DOI: 10.1007/s11095-018-2505-3
  • Peer Reviewed
• [Journal Article] A Novel Platform for Cancer Vaccines: Antigen-Selective Delivery to Splenic Marginal Zone B Cells via Repeated Injections of PEGylated Liposomes (2018)
  • Author(s): Shimizu Taro、Abu Lila Amr S.、Kawaguchi Yoshino、Shimazaki Yuna、Watanabe Yuki、Mima Yu、Hashimoto Yosuke、Okuhira Keiichiro、Storm Gert、Ishima Yu、Ishida Tatsuhiro
  • Journal Title: The Journal of Immunology Volume: 201 Issue: 10 Pages: 2969-2976
  • DOI: 10.4049/jimmunol.1701351
  • Peer Reviewed
• [Journal Article] In Vivo Knockdown of Pathogenic Proteins via Specific and Nongenetic Inhibitor of Apoptosis Protein (IAP)-dependent Protein Erasers (SNIPERs). (2017)
  • Author(s): Ohoka, N., Okuhira, K., Ito, M., Nagai, K., Shibata, N., Hattori, T., Ujikawa, O., Shimokawa, K., Sano, O., Koyama, R., Fujita, H., Teratani, M., Matsumoto, H., Imaeda, Y., Nara, H., Cho, N. & Naito, M.
  • Journal Title: J Biol Chem Volume: 292 Issue: 11 Pages: 4556-4570
  • DOI: 10.1074/jbc.m116.768853
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Improved anticancer effects of albumin-bound paclitaxel nanoparticle via augmentation of EPR effect and albumin-protein interactions using S-Nitrosated Human Serum Albumin Dimer. (2017)
  • Author(s): Kinoshita R, Ishima Y, Chuang VTG, Nakamura H, Fang J, Watanabe H, Shimizu T, Okuhira K, Ishida T, Maeda H, Otagiri M, Maruyama T.
  • Journal Title: Biomaterials. Volume: 140 Pages: 162-169
  • DOI: 10.1016/j.biomaterials.2017.06.021
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Targeted Degradation of Proteins Localized in Subcellular Compartments by Hybrid Small Molecules. (2017)
  • Author(s): Okuhira, K., Shoda, T., Omura, R., Ohoka, N., Hattori, T., Shibata, N., Demizu, Y., Sugihara, R., Ichino, A., Kawahara, H., Itoh, Y., Ishikawa, M., Hashimoto, Y., Kurihara, M., Itoh, S., Saito, H. & Naito, M.
  • Journal Title: Mol pharmacol Volume: 91 Issue: 3 Pages: 159-166
  • DOI: 10.1124/mol.116.105569
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Formation of stable nanodiscs by bihelical apolipoprotein A-I mimetic peptide (2016)
  • Author(s): Kariyazono, H., Nadai, R., Miyajima, R., Takechi-Haraya, Y., Baba, T., Shigenaga, A., Okuhira, K., Otaka, A., and Saito, H.
  • Journal Title: J. Peptide Sci. Volume: 22 Issue: 2 Pages: 116-122
  • DOI: 10.1002/psc.2847
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Development of a peptide-based inducer of nuclear receptors degradation. (2016)
  • Author(s): Demizu Y, Ohoka N, Nagakubo T, Yamashita H, Misawa T, Okuhira K, Naito M, Kurihara M.
  • Journal Title: Bioorg Med Chem Lett. Volume: 26 Issue: 11 Pages: 2655-2658
  • DOI: 10.1016/j.bmcl.2016.04.013
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Iowa Mutant Apolipoprotein A-I (ApoA-IIowa) Fibrils Target Lysosomes. (2016)
  • Author(s): Kameyama H., Nakajima H., Nishitsuji K., Mikawa S., Uchimura K., Kobayashi N., Okuhira K., Saito H., and Sakashita N.
  • Journal Title: Sci. Rep. Volume: 6 Issue: 1 Pages: 30391-30391
  • DOI: 10.1038/srep30391
  • NAID: 120006534966
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 多発性硬化症治療薬FTY720のアポリポタンパク質発現に対する影響 (2019)
  • Author(s): 小川真依，立花洸季，石田竜弘，奥平桂一郎
  • Organizer: 第58回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会
• [Presentation] アンチセンスのキャリア非依存性取り込み機構に寄与する膜タンパク質の検討 (2019)
  • Author(s): 内海彩花，佐々木澄美、楠本嵩志，吉田徳幸，石田竜弘，井上貴雄，奥平桂一郎
  • Organizer: 第58回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会
• [Presentation] プロテインノックダウン法を用いたチミジル酸合成酵素分解誘導剤開発 (2019)
  • Author(s): 有井紗由季，上田将弘，重永章，大髙章，石田竜弘，奥平桂一郎
  • Organizer: 第58回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会
• [Presentation] 天然物による膜トランスポーターABCA7の発現増強機構の解析 (2019)
  • Author(s): 楠本嵩志，堂前純子，田中直伸，柏田良樹，辻大輔，伊藤孝司，石田竜弘，奥平桂一郎
  • Organizer: 第92回日本生化学会大会
• [Presentation] 難治性膵臓がんへの高い移行性を有するアルブミンナノ粒子の開発 (2019)
  • Author(s): 平川尚樹，異島優，木下遼，清水太郎，丸山徹，奥平桂一郎，石田竜弘
  • Organizer: 日本薬剤学会第34年会
• [Presentation] 動脈硬化治療を指向した光制御型HDL構成ペプチドの開発 (2018)
  • Author(s): 宮下直樹、奥平桂一郎、川原遥華、津田雄介、森本恭平、辻耕平、重永章、大高章、石田竜弘
  • Organizer: 日本薬剤学会第33年会
• [Presentation] 共有結合型アルブミンナノ粒子をキャリアとしたナノDDS抗がん剤の開発及び有用性評価 (2018)
  • Author(s): 平川尚樹、木下遼、異島優、清水太郎、丸山徹、奥平桂一郎、石田竜弘
  • Organizer: 第34回日本DDS学会学術集会
• [Presentation] Xanthohumol を用いたDNAトランスフェクション効率の改善 (2018)
  • Author(s): 宮下直樹、奥平桂一郎、石田竜弘
  • Organizer: 第34回日本DDS学会学術集会
• [Presentation] HDL構成タンパク質分泌に対するスフィンゴシン-1-リン酸及びフィンゴリモドの影響 (2018)
  • Author(s): 立花洸季、田中保、小暮健太朗、石田竜弘、奥平桂一郎
  • Organizer: 第91回日本生化学会大会
• [Presentation] 共有結合型アルブミンナノ粒子を用いたセラノスティックナノDDS抗がん剤の開発 (2018)
  • Author(s): 平川尚樹、異島優、木下遼、清水太郎、丸山徹、奥平桂一郎、石田竜弘
  • Organizer: 第57回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会
• [Presentation] 人工HDLの化学的性状と体内動態への影響に関する検討 (2018)
  • Author(s): 金山忠史、奥平桂一郎、大川内健人、清水太郎、重永章、大高章、石田竜弘
  • Organizer: 第57回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会
• [Presentation] HDL構成タンパク質分泌に対するスフィンゴシン-1-リン酸及びフィンゴリモドの影響 (2018)
  • Author(s): 立花洸季、田中保、小暮健太朗、石田竜弘、奥平桂一郎
  • Organizer: 第57回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会
• [Presentation] 抗動脈硬化性タンパク質を利用した創薬への挑戦 (2018)
  • Author(s): 奥平桂一郎
  • Organizer: 日本薬学会第139年会
  • Invited
• [Presentation] 膜タンパク質ABCA7を増加させる新規天然物 (2018)
  • Author(s): 楠本嵩志、堂前純子、田中直伸、柏田良樹、辻大輔、伊藤孝司、石田竜弘、奥平桂一郎
  • Organizer: 日本薬学会第139年会
• [Presentation] apoA-I結合タンパク質AIBPの抗炎症活性発現メカニズムの検討 (2018)
  • Author(s): 末永翔平、金山忠史、橘茉里奈、楠本嵩志、杉原涼、西辻和親、辻田麻紀、石田竜弘、奥平桂一郎
  • Organizer: 日本薬学会第139年会
• [Presentation] 炎症モデルマウスにおけるapoA-I結合タンパク質AIBPの抗炎症作用の検討 (2018)
  • Author(s): 橘茉里奈、末永翔平、楠本嵩志、杉原涼、髙田春風、西辻和親、辻田麻紀、石田竜弘、奥平桂一郎
  • Organizer: 日本薬学会第139年会
• [Presentation] Sphingosine-1-phosphate (S1P) affects the secretion of high density lipoprotein (HDL)-constituent protein. (2018)
  • Author(s): Tachibana, K., Tanaka, T., Kogure, K., Ishida, T., Okuhira, K.
  • Organizer: 12th International Symposium on Nanomedicine
  • Int'l Joint Research
• [Presentation] ヒトアポA-I結合タンパク質AIBPの新規機能解明 (2018)
  • Author(s): 橘 茉里奈, 杉原 涼, 藤見 紀明, 西辻 和親, 坂下 直実, 辻田 麻紀, 石田 竜弘, 奥平 桂一郎
  • Organizer: 日本薬学会第138年会
• [Presentation] ヒトアポA-I結合タンパク質AIBPのLPS誘導性マクロファージ炎症反応抑制効果 (2017)
  • Author(s): 藤見紀明，杉原涼，西辻和親，坂下直実，辻大輔，伊藤孝司，辻田麻紀，奥平桂一郎
  • Organizer: 日本薬学会第137年会
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2017-03-24
• [Remarks] 徳島大学 教育研究者総覧
  • URL: http://pub2.db.tokushima-u.ac.jp/ERD/person/279489/profile-ja.html
• [Remarks] 製剤分子設計学分野ホームページ
  • URL: https://www.tokushima-u.ac.jp/ph/faculty/labo/szi/
• [Remarks] 徳島大学 教育研究者総覧
  • URL: http://pub2.db.tokushima-u.ac.jp/ERD/person/279489/work-ja.html
• [Remarks] 製剤分子設計学分野ホームページ
  • URL: http://www.tokushima-u.ac.jp/ph/faculty/labo/szi/
• [Remarks] 製剤分子設計学分野ホームページ
  • URL: http://www.tokushima-u.ac.jp/ph/faculty/labo/szi/achivement.html