Identification of genes involved in the vascular network formation though neuro-vascular interactions

2010 Fiscal Year Final Research Report

• Project/Area Number: 20590290
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Kanazawa Medical University
• Principal Investigator: YONEKURA Hideto Kanazawa Medical University, 医学部, 教授 (80240373)
• Co-Investigator(Kenkyū-buntansha): HATTA Toshihisa 金沢医科大学, 医学部, 教授 (20238025) ; YOSHITAKE Yoshino 金沢医科大学, 医学部, 准教授 (00150764)
• Project Period (FY): 2008 – 2010
• Keywords: 遺伝子 / 血管内皮細胞 / 神経-血管相互作用 / ミクロRNA / 可溶型VEGF受容体 / レンチウイルスベクター

Research Abstract

We identified genes which were reproducibly up-regulated in HMVEC by the co-culture with dorsal root ganglion neurons and human microvascular endothelial cells (HMVEC). We found that hypoxia down-regulated soluble VEGF receptor-1 (soluble Flt-1, sFlt-1) expression in HMVEC and identified cis-elements that regulated sFlt-1 mRNA 3'-end processing. We found significantly reduced expression of esRAGE, a decoy receptor for amyloid β, in the hippocampal tissues from Alzheimer's disease brains by immunohistochemical analysis. We revealed that HMVEC expressed over 20 microRNAs including miR21. We injected lentiviral vectors into embryonic mouse skin and brain, and confirmed the expression of the introduced genes. We developed an assay method for esRAGE mRNA and an esRAGE transgenic mouse, and applied for patents for them.

Research Products

• [Journal Article] Hypoxia down-regulates sFlt-1 (sVEGFR-1) expression in human microvascular endothelial cells by a mechanism involving mRNA alternative processing. (2011)
  • Author(s): Ikeda T, Sun L, Tsuruoka N, Ishigaki Y, Yoshitomi Y, Yoshitake Y, Yonekura H.
  • Journal Title: Biochem.J. 436 Pages: 399-407
  • Peer Reviewed
• [Journal Article] Septic shock is associated with receptor for advanced glycation endproducts (RAGE) ligation of LPS. (2011)
  • Author(s): Yamamoto Y, Harashima A, Saito H, Tsuneyama K, Munesue S, Motoyoshi S, Han D, Watanabe T, Asano M, Takasawa S, Okamoto H, Shimura S, Karasawa T, Yonekura H, Yamamoto H.
  • Journal Title: J.Immunol. 186 Pages: 3248-57
  • Peer Reviewed
• [Journal Article] Ultraviolet B-induced expression of amphiregulin and growth differentiation factor 15 in human lens epithelial cells. (2011)
  • Author(s): Osada H, Yoshitake Y, Ikeda T, Ishigaki Y, Takata T, Tomosugi N, Sasaki H, Yonekura H.
  • Journal Title: Mol.Vis. 17 Pages: 159-169
  • Peer Reviewed
• [Journal Article] Identification of the COL2A1 Mutation in Patients with Type I Stickler Syndrome Using RNA from Freshly Isolated Peripheral White Blood Cells. (2011)
  • Author(s): Yaguchi H, Ikeda T, Osada H, Yoshitake Y, Sasaki H, Yonekura H.
  • Journal Title: Genet.Test.Mol.Biomarkers. 15 Pages: 231-237
  • Peer Reviewed
• [Journal Article] Regulation of alternative splicing of the receptor for advanced glycation endproducts (RAGE) through G-rich cis-elements and heterogenous nuclear ribonucleoprotein (hnRNP) H. (2010)
  • Author(s): Ohe K, Watanabe T, Harada SI, Munesue S, Yamamoto Y, Yonekura H, Yamamoto H.
  • Journal Title: J.Biochem. 147 Pages: 651-659
  • Peer Reviewed
• [Journal Article] Identification of HITS, anewly identified TU3A/DDR1 family of protein (FAM107B), in cancer cells by heat shock stimulation. (2010)
  • Author(s): Nakajima H, Ishigaki Y, Xia Q, Ikeda T, Yoshitake Y, Yonekura H, Nojima T, Tanaka T, Umehara H, Tomosugi N, Takada T, Shimasaki T, Nakaya N, Sato I, Koizumi K, Kawakami K, Minamoto T, Motoo Y.
  • Journal Title: Int.J.Oncol. 37 Pages: 583-593
  • Peer Reviewed
• [Journal Article] Maternal leukemia inhibitory factor (LIF) promotes fetal neurogenesis via a LIF-ACTH-LIF signaling relay pathway. (2010)
  • Author(s): Simamura E, Shimada H, Higashi N, Uchishiba M, Otani H, Hatta T.
  • Journal Title: Endocrinology 151 Pages: 1853-1862
  • Peer Reviewed
• [Journal Article] Paraquat toxicity induced by voltage-dependent anion channel 1 acting as an NADH-dependent oxidoreductase. (2009)
  • Author(s): Shimada H, Hirai K-I, Simamura E, Hatta T, Iwakiri H, Mizuki K, Hatta T, Sawasaki T, Matsunaga S, Endo Y, Shimizu S.
  • Journal Title: J.Biol.Chem. 284 Pages: 28642-28649
  • Peer Reviewed
• [Journal Article] Solution structure of the variable-type domain of the receptor for advanced glycation end products : new insight into AGE-RAGE interaction. (2008)
  • Author(s): Matsumoto S, Yoshida T, Murata H, Harada S, Fujita N, Nakamura S, Yamamoto Y, Watanabe T, Yonekura H, Yamamoto H, Ohkubo T, Kobayashi Y.
  • Journal Title: Biochemistry 47 Pages: 12299-12311
  • Peer Reviewed
• [Journal Article] Bioreductive activation of quinine antitumor drugs by mitochondrial voltage-dependent anion channel 1. (2008)
  • Author(s): Simamura E, Shimada H, Ishigaki Y, Hatta T, Higashi N, Hirai K-I.
  • Journal Title: Anat.Sci.Int. 83 Pages: 261-266
  • Peer Reviewed
• [Journal Article] Mitochondrial voltage-dependent anion channels (VDACs) as novel pharmacological targets for anti-cancer agents. (2008)
  • Author(s): Simamura E, Shimada H, Hatta T, Hirai K-I.
  • Journal Title: J.Bioenerg.Biomembr. 40 Pages: 213-217
  • Peer Reviewed
• [Journal Article] Right vertebral artery as the fourth branch of the aortic arch. (2008)
  • Author(s): Higashi N, Shimada H, Simamura E, Hatta T.
  • Journal Title: Anat.Sci.Int. 83 Pages: 314-318
  • Peer Reviewed
• [Presentation] Soluble VEGFR-1 production is down-regulated under hypoxia in human microvascular endothelial cells by a mechanism involving alternative mRNA 3'-end processing. (2011)
  • Author(s): Ikeda T, Yoshitomi Y, Ishigaki Y, Yoshitake Y, Yonekura H
  • Organizer: 日本分子生物学会第11回春季シンポジウム・金沢国際がん生物学シンポジウム
  • Place of Presentation: 石川県立音楽堂(金沢市)
  • Year and Date: 20110525-20110526
• [Presentation] 低酸素刺激による微小血管内皮細胞の可溶型VEGF受容体(可溶型Flt-1)産生の抑制 (2011)
  • Author(s): 池田崇之、吉冨泰夫、石垣靖人、吉竹佳の、米倉秀人
  • Organizer: 第83回日本生化学会北陸支部会
  • Place of Presentation: 金沢大学角間キャンパス(金沢市)
  • Year and Date: 2011-05-28
• [Presentation] 低酸素状態は3'端プロセシングを制御することによって血管内皮細胞での可溶型VEGF受容体(可溶型Flt-1)産生を減少させる (2010)
  • Author(s): 池田崇之、吉竹佳の、米倉秀人
  • Organizer: 第83回日本生化学会大会・第33回日本分子生物学会年会・合同大会
  • Place of Presentation: 神戸ポートアイランド(神戸市)
  • Year and Date: 20101207-20101210
• [Presentation] UVB曝露ストレスによる水晶体上皮細胞のAmphiregulin発現の上昇 (2010)
  • Author(s): 吉竹佳の、長田ひろみ、池田崇之、石垣靖人、高田尊信、友杉直久、佐々木洋、米倉秀人
  • Organizer: 第83回日本生化学会大会・第33回日本分子生物学会年会・合同大会
  • Place of Presentation: 神戸ポートアイランド(神戸市)
  • Year and Date: 20101207-20101210
• [Presentation] Alteration of gene expression profiles in the fetal cerebrum after injection of leukemia inhibitory factor into dams. (2010)
  • Author(s): Hatta T, Shimada H, Simamura E, Ishigaki Y, Higashi N, Tatsuno T, Takano F.
  • Organizer: Society for NEUROSCIENCE 2010
  • Place of Presentation: San Diego, USA
  • Year and Date: 20101100
• [Presentation] 可溶型VEGF受容体(可溶型Flt-1)産生を制御する選択的3'端プロセシングメカニズムの解明 (2010)
  • Author(s): 池田崇之、吉竹佳の、米倉秀人
  • Organizer: 第12回日本RNA学会年会
  • Place of Presentation: 一橋記念講堂(東京都)
  • Year and Date: 20100727-20100729
• [Presentation] Enemies and friends within in the pathogenesis and prevention of diabetic vascular complications. (2010)
  • Author(s): Yamamoto H, Watanabe T, Yamamoto Y, Yonekura H, Munesue S, Ohe K, Sugihara T, Saito H, Motoyoshi S, Han D, Win MTT, Abouzed TKMI, Ohara T.
  • Organizer: The 4th International HMGB1 Symposium SIGNALS OF TISSUE DAMAGE (Invited Lecture)
  • Place of Presentation: Helsinki, Finland
  • Year and Date: 20100620-20100623
• [Presentation] The role of AGE in atherosclerosis. (2010)
  • Author(s): Yamamoto H, Watanabe T, Yamamoto Y, Yonekura H, Munesue S, Ohe K, Sugihara T, Saito H, Motoyoshi S, Han D, Win MTT, Abouzed TKMI, Ohara T.
  • Organizer: XXth World Congress of the International Society for Heart Research (Invited Lecture)
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 20100513-20100516
• [Presentation] UVB暴露による培養水晶体上皮細胞での遺伝子発現変化 (2010)
  • Author(s): 長田ひろみ、吉竹佳の、石垣靖人、池田崇之、山代陽子、米倉秀人、佐々木洋
  • Organizer: 第114回日本眼科学会総会
  • Place of Presentation: 名古屋国際会議場(名古屋市)
  • Year and Date: 20100415-20100418
• [Presentation] UVB暴露による培養水晶体上皮細胞での遺伝子発現変化 (2010)
  • Author(s): 長田ひろみ、吉竹佳の、石垣靖人、池田崇之、山代陽子、米倉秀人、佐々木洋
  • Organizer: 第36回水晶体研究会
  • Place of Presentation: 帝京大学(東京都)
  • Year and Date: 20100109-20100110
• [Presentation] Enemies and Friends Within in the Pathogenesis and Prevention of Diabetic Vasculopathy. (2009)
  • Author(s): Yamamoto H, Watanabe T, Yamamoto Y, Yonekura H, Munesue S, Ohe K, Sugihara T, Saito H, Motoyoshi S, Han D, Win MTT.
  • Organizer: 2009 International Conference on Vascular Biology (Invited Lecture)
  • Place of Presentation: Zhunan, Taiwan
  • Year and Date: 20091029-20091031
• [Presentation] 患者末梢血白血球RNAを用いたStickler症候群原因遺伝子COL2A1の新規3'splice site変異の同定 (2009)
  • Author(s): 米倉秀人、池田崇之、吉竹佳の、矢口裕基、長田ひろみ、佐々木洋
  • Organizer: 第82回日本生化学会大会
  • Place of Presentation: 神戸ポートアイランド(神戸市)
  • Year and Date: 20091021-20091024
• [Presentation] 2型リアノジン受容体遺伝子にはGG-AG配列で切断されるイントロンが存在する (2009)
  • Author(s): 池田崇之、野口直哉、吉川雄朗、宇留野晃、那谷耕司、高澤伸、岡本宏、米倉秀人、菅原明
  • Organizer: 第82回日本生化学会大会
  • Place of Presentation: 神戸ポートアイランド(神戸市)
  • Year and Date: 20091021-20091024
• [Presentation] G-triplet in intron 9 activate the membrane type RAGE splicing via interaction with hnRNP. (2009)
  • Author(s): Ohe K, Watanabe T, Harada S, Munesue S, Yamamoto Y, Yonekura H, Yamamoto H.
  • Organizer: 第82回日本生化学会大会
  • Place of Presentation: 神戸ポートアイランド(神戸市)
  • Year and Date: 20091021-20091024
• [Presentation] Maternal leukemia inhibitory factor enhances proliferation of neuronal progenitors of forebrain in rat fetuses. (2009)
  • Author(s): Hatta T, Simamura E, Shimada H, Uchishiba M, Higashi N.
  • Organizer: Society for NEUROSCIENCE 2009
  • Place of Presentation: Chicago, USA
  • Year and Date: 20091000
• [Presentation] Leukemia inhibitory factor level in cerebrospinal fluid is elevated via placental adrenocorticotropic hormone in rat fetuses. (2009)
  • Author(s): Simamura E, Shimada H, Higashi N, Otani H, Hatta T.
  • Organizer: Society for NEUROSCIENCE 2009
  • Place of Presentation: Chicago, USA
  • Year and Date: 20091000
• [Presentation] Maternal LIF contributes to fetal development via a LIF-ACTH-LIF signaling relay pathway. (2009)
  • Author(s): Hatta T, Simamura E, Otani H.
  • Organizer: International Symposium Analyses of Developmental Phenomena : Toward the elucidation of the developmental origins of diseases
  • Place of Presentation: Izumo, Japan
  • Year and Date: 20091000
• [Presentation] 末梢血白血球RNAを用いたStickler症候群原因遺伝子の変異部位の同定 (2009)
  • Author(s): 長田ひろみ、矢口裕基、佐々木洋、孫立、吉竹佳の、米倉秀人
  • Organizer: 第113回日本眼科学会総会
  • Place of Presentation: 東京国際フォーラム(東京都)
  • Year and Date: 20090416-20090419
• [Presentation] 血管内皮細胞におけるRAGE mRNA選択的スプライシングの制御機構.BMB2008 (2008)
  • Author(s): 大江和代、渡邉琢夫、原田真市、棟居聖一、山本靖彦、米倉秀人、山本博
  • Organizer: 第31回日本分子生物学会年会・第81回日本生化学会大会 合同大会
  • Place of Presentation: 神戸ポートアイランド(神戸市)
  • Year and Date: 20081209-20081212
• [Presentation] AβとRAGE (receptor for advanced glycation endproducts)の相互作用におけるesRAGE (endogenous secretory RAGE)の役割.BMB2008 (2008)
  • Author(s): 杉原崇大、棟居聖一、山本靖彦、櫻井繁、渡邉琢夫、原田真市、米倉秀人、山本博
  • Organizer: 第31回日本分子生物学会年会・第81回日本生化学会大会 合同大会
  • Place of Presentation: 神戸ポートアイランド(神戸市)
  • Year and Date: 20081209-20081212
• [Presentation] An approach toward identification of cis-RNA elements and trans-factors involved in alternative splicing of RAGE gene transcript. (2008)
  • Author(s): Ohe K, Watanabe T, Harada S, Munesue S, Yamamoto Y, Yonekura H, Yamamoto H.
  • Organizer: The 6th Korea-Japan Joint Symposium on Vascular Biology
  • Place of Presentation: Kanazawa, Japan
  • Year and Date: 20081203-20081205
• [Presentation] Regulatory mechanisms of alternative 3'-end processing of soluble VEGF receptor pre-mRNA in vascular endothelial cells. (2008)
  • Author(s): Yonekura H, Tsuruoka N, Yoshitake Y, Sun L, Watanabe T, Yamamoto H.
  • Organizer: The 33rd FEBS Congress & 11th IUBMB Conference
  • Place of Presentation: Athens, Greek
  • Year and Date: 20080628-20080703
• [Presentation] Micro-RNAs expressed in human microvascular endothelial cells. (2008)
  • Author(s): 吉竹佳の, 米倉秀人
  • Organizer: The 33rd FEBS Congress & 11th IUBMB Conference
  • Place of Presentation: Athens, Greek
  • Year and Date: 20080628-20080703
• [Presentation] ヒト骨芽細胞のコラーゲン産生およびラットの骨折治癒に対するコラーゲン・トリペプチドの効果 (2008)
  • Author(s): 酒井康夫、鶴岡直樹、吉竹佳の、米倉秀人、沼田徳暁
  • Organizer: 第62回日本栄養食糧学会
  • Place of Presentation: 女子栄養大学坂戸キャンパス(坂戸市)
  • Year and Date: 20080502-20080504
• [Patent(Industrial Property Rights)] esRAGE過剰発現マウス (2009)
  • Inventor(s): 渡邉琢夫,山本博,山本靖彦,棟居聖一,杉原崇大,米倉秀人,櫻井繁
  • Industrial Property Rights Holder: 国立大学法人金沢大学
  • Industrial Property Number: 特許,特願2009-120572
  • Filing Date: 2009-05-19
• [Patent(Industrial Property Rights)] RAGE遺伝子の2種類のスプライシングバリアントを区別して増幅可能なプライマーセット及びプローブ (2009)
  • Inventor(s): 渡邉琢夫,棟居聖一,山本靖彦,山本博,大江和代,米倉秀人
  • Industrial Property Rights Holder: 国立大学法人金沢大学,学校法人金沢医科大学
  • Industrial Property Number: 特許,特願2009-87418
  • Filing Date: 2009-03-31
• [Patent(Industrial Property Rights)] 可溶型RAGEタンパク質(soluble rage protein) (2009)
  • Inventor(s): 山本博,米倉秀人,山本靖彦,櫻井繁,渡辺琢夫
  • Industrial Property Rights Holder: 金沢大学長
  • Industrial Property Number: 特許,US7485697
  • Acquisition Date: 2009-02-03
• [Patent(Industrial Property Rights)] AGE-RAGE拮抗剤 (2008)
  • Inventor(s): 山本博,米倉秀人,渡邉琢夫,山本靖彦,櫻井繁
  • Industrial Property Rights Holder: 国立大学法人金沢大学
  • Industrial Property Number: 特許,特許第4143716号
  • Acquisition Date: 2008-06-27
• [Patent(Industrial Property Rights)] 可溶型RAGEタンパク質(SOLUBLE RAGE PROTEIN) (2008)
  • Inventor(s): 山本博,米倉秀人,山本靖彦,櫻井繁,渡辺琢夫
  • Industrial Property Rights Holder: 金沢大学長
  • Industrial Property Number: 特許,EP01380593B1
  • Acquisition Date: 2008-05-07