A novel signal reception mechanism by oligomerization of RAGE and gamma-secretase

2011 Fiscal Year Final Research Report

• Project/Area Number: 21590304
• 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 University
• Principal Investigator: WATANABE Takuo 金沢大学, 医学系, 准教授 (40303268)
• Co-Investigator(Kenkyū-buntansha): YAMAMOTO Hiroshi 金沢大学, 医学系, 教授 (00115198) ; MUNESUE Seiichi 金沢大学, 医学系, 助教 (10399040)
• Project Period (FY): 2009 – 2011
• Keywords: RAGE / オリゴマー化 / γ-セクレターゼ / マトリックスメタロプロテアーゼ / cAMP / PDE阻害剤

Research Abstract

(1) We found a gamma-secretase inhibitor suppressed RAGE signaling by unknown mechanism other than inhibition of gamma-secretase activity.(2) We clarified that the cAMP exerts the inhibitory effects on RAGE signaling by enhancement of MMP9-mediated RAGE shedding that leads to decrease of membrane-bound form RAGE and increase of decoy/soluble form RAGE.(3) We showed the possibility that the PDE inhibitor, which cause enforcement of cAMP signaling could suppress the inflammatory bowel disease using mouse model.

Research Products

• [Journal Article] CCR5 Plays a Critical Role in Obesity-Induced Adipose Tissue In flammation and Insulin Resistance by Regulating Both Macrophage Recruitment andM1/M2 Status (2012)
  • Author(s): Kitade H, Sawamoto K, Nagashimada M, Inoue H, Yamamoto Y, Sai Y, Takamura T, Yamamoto H, Miyamoto KI, Ginsberg HN, Mukaida N, Kaneko S, Ota T
  • Journal Title: Diabetes Epub
  • Peer Reviewed
• [Journal Article] RAGE mediates vascular injury and inflammation after global cerebral ischemia (2012)
  • Author(s): Kamide T, Kitao Y, Takeichi T, Okada A, Mohri H, Schmidt AM, Kawano T, Munesue S, Yamamoto Y, Yamamoto H, Hamada J, Hori O
  • Journal Title: Neurochem Int Volume: 60 Pages: 220-228
  • Peer Reviewed
• [Journal Article] Diabetes alters subsets of endothelial progenitorcells that reside in blood, bone marrow, and spleen (2011)
  • Author(s): Saito H, Yamamoto Y, Yamamoto H
  • Journal Title: Am J Physiol Cell Physiol Volume: 302 Pages: C892-901
  • Peer Reviewed
• [Journal Article] Regulation of RAGE for attenuating progression of diabetic vascular complications (2011)
  • Author(s): Win MT, Yamamoto Y, Munesue S, Saito H, Han D, Motoyoshi S, Kamal T, Ohara T, Watanabe T, Yamamoto H
  • Journal Title: Exp. Diabetes Res. Epub
  • Peer Reviewed
• [Journal Article] Endogenous Secretory Receptor for AGE Inhibits Amyloid-β^<1-42> Uptake into Mouse Brain J (2011)
  • Author(s): Sugihara T, Munesue S, Yamamoto Y, Sakaurai S, Akhter N, Kitamura Y, Shiba K, Watanabe T, Yonekura H, Hayashi Y, Hamada J, Yamamoto H
  • Journal Title: Alzheimer's Dis Volume: 28 Pages: 709-710
  • Peer Reviewed
• [Journal Article] Gabazza EC : Inhibition of allergic bronchial asthma by thrombomodulin is mediated bydendritic cells (2011)
  • Author(s): Takagi T, Taguchi O, Toda M, Ruiz DB, Bernabe PG, D' Alessandro-Gabazza CN, MiyakeY, Kobayashi T, Aoki S, Chiba F, Yano Y, Conway EM, Munesue S, Yamamoto Y, Yamamoto H, Suzuki K, Takei Y, Morser Y
  • Journal Title: Am. J. Respir Crit. Care Med Volume: 183 Pages: 31-42
  • Peer Reviewed
• [Journal Article] OxLDL-mediated survival of macrophages doesnot require LDL internalization or signalling bymajor pattern recognition receptors (2011)
  • Author(s): Riazy M, Chen JH, Yamamato Y, YamamatoH, Duronio V, Steinbrecher UP
  • Journal Title: Biochem Cell Biol Volume: 89 Pages: 387-395
  • Peer Reviewed
• [Journal Article] Receptor foradvanced glycation end-products(RAGE) provides a link between genetic susceptibility and environmental factors in type 1 diabetes (2011)
  • Author(s): Forbes JM, Soderlund J, Yap FY, Knip M, Andrikopoulos S, Ilonen J, Simell O, Veijola R, Sourris KC, Coughlan MT, Forsblom C, Slattery R, Grey ST, Wessman M, Yamamoto H, BierhausA, Cooper ME, Groop PH
  • Journal Title: Diabetologia Volume: 54 Pages: 1586-1587
  • Peer Reviewed
• [Journal Article] Receptor for advanced glycation end productsbinds to phosphatidylserine and assists in theclearance of apoptotic cells (2011)
  • Author(s): He M, Kubo H, Morimoto K, Fujino N, Suzuki T, Takahasi T, Yamada M, Yamaya M, Maekawa T, Yamamoto Y, Yamamoto H
  • Journal Title: EMBO Rep Volume: 12 Pages: 358-364
  • Peer Reviewed
• [Journal Article] Septic shock is associated with receptor for advanced glycation end products 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, YamamotoH
  • Journal Title: J. Immunol Volume: 186 Pages: 3248-3257
  • Peer Reviewed
• [Journal Article] The effects of receptor for advanced glycation endproducts(RAGE) on bone metabolism underphysiological and diabetic condition (2010)
  • Author(s): Hamada Y, Kitazawa S, Kitazawa R, Kono K, Goto S, Komaba H, Fujii H, Yamamoto Y, Yamamoto H, Usami M, Fukagawa M
  • Journal Title: Endocrine inpress
  • Peer Reviewed
• [Journal Article] Glycation of a food allergen by the Maillard reaction enhances its T-cell immunogenicity (2010)
  • Author(s): Ichmann A, Burgdorf S, Scheurer S, WaiblerZ, Nagai R, Wellner A, Yamamoto Y, YamamotoH, Henle T, Kurts C, Kalinke U, Vieths S, Toda M
  • Journal Title: J. Allergy Clin. Immunol Volume: 125 Pages: 175-183
  • Peer Reviewed
• [Journal Article] High-mobility group box 1 isinvolved in the initial events of early loss of transplanted islets in mice (2010)
  • Author(s): Matsuoka N, Itoh T, Watarai H, Sekine-Kondo E, Nagata N, Okamoto K, Mera T, Yamamoto H, Yamada S, Maruyama I, TaniguchiM, Yasunami Y
  • Journal Title: J. Clin. Invest Volume: 120 Pages: 735-743
  • Peer Reviewed
• [Journal Article] Receptor for advanced glycationend-products(RAGE) regulation of adiposity and adiponectin is associated with atherogenesis inapo E-deficient mouse (2010)
  • Author(s): Ueno H, Koyama H, Shoji T, Kurato M, Fukumoto S, Tanaka S, Otsuka Y, Mima Y, Morioka T, Mori K, Shioi A, Yamamoto H, InabaM, Nishizawa Y
  • Journal Title: Atherosclerosis Volume: 211 Pages: 431-436
  • Peer Reviewed
• [Journal Article] Recepter for AGEs(RAGE) blockade may exert itsrenoprotective effects in patients with diabetic nephropathy via induction of the angiotensin type2(AT2) receptor (2010)
  • Author(s): Sourris KC, Morley AL, Koitka A, Samuel P, Coughlan MT, Penfold SA, Tomas MC, BierhausA, Nawroth PP, Yamamoto H, Allen TJ, WaltherT, Hussain T, Cooper ME, Forbes JM
  • Journal Title: Diabetologia Volume: 53 Pages: 2442-2451
  • Peer Reviewed
• [Journal Article] Blockade of endothelial-mesenchymal-transitionby a Smad3 inhibitor delays the early development of streptozotocin-induced diabetic nephropathy (2010)
  • Author(s): Li J, Qu X, Yao J, Caruana G, Ricardo SD, Yamamoto Y, Yamamoto H, Bertram JF
  • Journal Title: Diabetes Volume: 59 Pages: 2612-2624
  • Peer Reviewed
• [Journal Article] Regulation of alternative splicing of the receptorfor advanced glycation endproducts(RAGE) through G-rich cis-elements and heterogenous nuclear ribonucleoprotein(hnRNP) H. J (2010)
  • Author(s): Ohe K, Watanabe T, Harada S, Munesue S, Yamamoto Y, Yonekura H, Yamamoto H
  • Journal Title: Biochem Volume: 147 Pages: 651-659
  • Peer Reviewed
• [Journal Article] Spontaneous bone loss in RIP-iNOS transgenic mouse : a mouse model for diabetes-mediated osteopenia/osteoporosis (2009)
  • Author(s): Mi QS, Yan SL, Wang ZZ, Ding KH, Li C, Wang L, Zhou L, Yamamoto Y, Yamamoto H, Okamoto H, Isales C
  • Journal Title: Cell Cycle Volume: 8 Pages: 4179-4181
  • Peer Reviewed
• [Journal Article] Deletion of RAGE causes hyperactivity and increased sensitivity to auditory stimuli in mice (2009)
  • Author(s): Sakatani S, Yamada K, Homma C, Munesue S, Yamamoto Y, Yamamoto H, Hirase H
  • Journal Title: PLoS ONE Volume: 4 Pages: e8309
  • Peer Reviewed
• [Journal Article] RAGE mediates oxidizedLDL-induced pro-inflammatory effects and atherosclerosis in non-diabetic LDL receptor-deficient mice (2009)
  • Author(s): Sun L, Ishida T, Yasuda T, Kojima Y, HonjoT, Yamamoto Y, Yamamoto H, Ishibashi S, Hirata K, Hayashi Y
  • Journal Title: Cardiovascular Research Volume: 82 Pages: 371-381
  • Peer Reviewed
• [Presentation] cAMP Exerts Anti-Inflammatory Effects by Controling RAGE Isoform Biogenesis (2010)
  • Author(s): Soh Motoyoshi, Yasuhiko Yamamoto, SeiichiMunesue, Takuo Watanabe, Hiroshi Yamamoto
  • Organizer: 70^<th> American Diabetes Association ScientificSessions
  • Place of Presentation: Orland USA
  • Year and Date: 20100625-29
• [Presentation] Enemies andfriends within in the pathogenesis and preventionof diabetic vascular complications (2010)
  • Author(s): Yamamoto H, Watanabe T, Yamamoto Y, Yonekura H, Munesue S, Ohe K, Sugihara T1, Saito H, Motoyoshi S, Han D, Win MTT, Abou-Zed TK, and Ohara T
  • Organizer: 4^<th> International HMGB1 Symposium-Signals of Tissue Damage
  • Place of Presentation: Helsinki, Finland
  • Year and Date: 20100620-23
• [Book] 糖化による疾患と抗糖化食品・素材序編-2、1編-5、1編-12 (2010)
  • Author(s): 山本博、久保田浩之、杉原崇大、山本靖彦
  • Publisher: シーエムシー出版
• [Book] 生命への鍵「ステロイド」-その研究に貢献した生化学者と臨床家たち (2009)
  • Author(s): 竹田亮祐、宮森勇、山本博
  • Publisher: 前田書店
• [Patent(Industrial Property Rights)] アルツハイマー病の診断方法 (2012)
  • Inventor(s): 山本博,米倉秀人,渡邉琢夫,山本靖彦,常山幸一,赤津裕康,川口誠,三浦裕
  • Industrial Property Rights Holder: 国立大学法人金沢大学
  • Industrial Property Number: 特許、第4933159号
  • Filing Date: 2012-02-24
• [Patent(Industrial Property Rights)] RAGEポリペプチドの新規用途 (2012)
  • Inventor(s): 山本博、米倉秀人、渡邉琢夫、山本靖彦、原島愛、唐澤忠宏、志村敏史
  • Industrial Property Rights Holder: 国立大学法人金沢大学
  • Industrial Property Number: 特許、第4951755号
  • Filing Date: 2012-03-23
• [Patent(Industrial Property Rights)] 早期肺癌の術後予後検査方法 (2010)
  • Inventor(s): 久保裕司,小林誠一,鈴木貴,鈴木聡,石沢興太,山本博,米倉秀人,渡辺琢夫,山本靖彦
  • Industrial Property Rights Holder: 国立大学法人金沢大学
  • Industrial Property Number: 特許、第4779115号
  • Filing Date: 2010-07-15
• [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: 特願、2009-120572
  • Filing Date: 2009-05-19