Pathophysiological roles of nardilysin, critical factor for axonal maturation and myelination

2013 Fiscal Year Final Research Report

• Project/Area Number: 23300117
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neuroscience in general
• Research Institution: Kyoto University
• Principal Investigator: NISHI Eiichiro 京都大学, 医学(系)研究科(研究院), 准教授 (30362528)
• Co-Investigator(Kenkyū-buntansha): OHNO Mikiko (10583198)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Keywords: メタロプロテアーゼ / 髄鞘形成 / 交感神経 / 循環動態

Research Abstract

We originally identified a metalloendopeptidase nardylisin (NRDc) as a binding partner of HB-EGF and reported that NRDc enhances ectodomain shedding of multiple membrane proteins. We generated NRDc-deficient (Nrd1-/-) mice and demonstrated that NRDc critically regulates axonal maturation and myelination in the central and peripheral nervous system through the regulation of neuregulin-1 shedding.
Here, we demonstrate that Nrd1-/- mice show severe hypotension and bradycardia. In spite of these phenotypes, analysis of heart rate variability and serum catecholamine levels revealed that sympathetic activity is upregulated in Nrd1-/- mice. Furthermore, Nrd1-/- mice showed abnormal sympathetic innervation patterning. Pharmacological blocking of autonomic nervous system showed that the intrinsic heart rate of Nrd1-/- mice was significantly decreased. In conclusion, NRDc critically regulates circulatory dynamics through modulating intrinsic heart rate and cardiac sympathetic innervation.

Research Products

• [Journal Article] Critical roles of nardilysin in the maintenance of body temperature homeostasis (2014)
  • Author(s): Hiraoka Y, Matsuoka T, Ohno M, Nakamura K, Saijo S, Matsumura S, Nishi K, Sakamoto J, Chen Po-Min, Inoue K, Fushiki T, Kita T, Kimura T and Nishi E
  • Journal Title: Nat. Commun Volume: 5 Pages: 3224
  • DOI: 10.1038/ncomms4224
• [Journal Article] Nardilysin prevents amyloid plaque formation by enhancing a-secretase activity in an Alzheimer's disease mouse model (2014)
  • Author(s): Ohno M, Hiraoka Y, Lichtenthaler S, Nishi K, Saijo S, Matsuoka T, Tomimoto H, Araki W, Takahashi R, Kita T, Kimura T and Nishi E
  • Journal Title: Neurobiol Aging Volume: 35 Pages: 213-22
  • DOI: 10.1016/j.neurobiolaging.2013.07.014
• [Journal Article] Identification and Characterization of Nardilysin as a Novel Dimethyl H3K4 Binding Protein Involved in Transcriptional Regulation (2012)
  • Author(s): Li J, Chu M, Wang S, Chan D, Qi S, Wu M, Zhou Z, Li Z, Nishi E, Qin J and Wong J
  • Journal Title: J Biol Chem Volume: 287 Pages: 10089-98
  • DOI: 10.1074/jbc.M111.313965
• [Journal Article] Nardilysin and ADAM proteases promote gastric cancer cell growth by activating intrinsic cytokine signaling via enhanced ectodomain shedding of TNF-a (2012)
  • Author(s): Kanda K, Komekado H, Sawabu T, Ishizu S, Nakanishi Y, Nakatsuji M, Akitake-Kawano R, Ohno M, Hiraoka Y, Kawada M, Kawada K, Sakai Y, Matsumoto K, Kunichika M, Kimura T, Seno H, Nishi E, and Chiba T
  • Journal Title: EMBO Mol Med Volume: 4 Pages: 396-411
  • DOI: 10.1002/emmm.201200216
• [Presentation] Nardilysin Regulates Adaptive Thermogenesis and Body Temperature Homeostasis through Modulation of PGC-1α (2014)
  • Author(s): Saijo S, Hiraoka Y, Matsuoka T, Ohno M, Nakamura K, Matsumura S, Nishi K, Sakamoto J, Chen P, Kita T, Kimura T, Nishi E
  • Organizer: 第78回日本循環器学会総会
  • Place of Presentation: 東京
  • Year and Date: 2014-03-23
• [Presentation] Nardylisin controls glucose metabolism through the regulation of insulin secretion (2014)
  • Author(s): Nishi K, Sato Y, Ohno M, Hiraoka Y, Saijyo S, Sakamoto J, Chen P, Kita T, Inagaki N, Kimura T, Nishi E
  • Organizer: 第78回日本循環器学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2014-03-21
• [Presentation] Nardilysin is Involved in Pressure Overload-induced Dysfunction and Fibrosis of Left Ventricle (2014)
  • Author(s): Sakamoto J, Chen PM, Saijo S, Nishi K, Ohno M, Kita T, Kimura T, Nishi E
  • Organizer: 第78回日本循環器学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2014-03-21
• [Presentation] Critical roles of a metalloendopeptidase nardilysin in cold-induced adaptive thermogenesis (2013)
  • Author(s): Hiraoka Y, T. Matsuoka, M. Ohno, K. Nishi, K. Nakamura, K, Kita, T. Kimura and E. Nishi
  • Organizer: ASCB (American Society for Cell Biology)
  • Place of Presentation: New Orleans, USA
  • Year and Date: 20131214-18
• [Presentation] アルツハイマー病におけるナルディライジンの意義 (2013)
  • Author(s): 大野 美紀子, 平岡 義範, Lichtenthaler Stefan F, 富本 秀和, 荒木 亙, 高橋 良輔, 坂本 二郎
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 神戸
  • Year and Date: 20131204-06
• [Presentation] ナルディライジンは PGC-1αを制御することで体温恒常性維持機構と適応熱産生を調節する (2013)
  • Author(s): 西城さやか, 平岡 義範, 松岡 龍彦, 大野美紀子,中村 和弘, 松村 成暢, 西 清人, 坂本二郎, 陳 博敏, 北 徹, 木村 剛, 西英一郎
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 神戸
  • Year and Date: 20131203-06
• [Presentation] ナルディラインジンはグルコース応答性インスリン分泌を制御する (2013)
  • Author(s): 西 清人, 佐藤 雄一, 大野 美紀子, 平岡 義範, 西城 さやか, 坂本 二郎, 陳 博敏, 松岡龍彦, 北 徹, 稲垣 暢也, 木村 剛, 西 英一郎
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 神戸
  • Year and Date: 20131203-06
• [Presentation] Nardilysin is a critical regulator of insulin secretion and glucose metabolism | (2013)
  • Author(s): Nishi K, Sato Y, Ohno M, Hiraoka Y, Saijyo S, Sakamoto J, Chen P, Kita T, Inagaki N, Kimura T, Nishi E
  • Organizer: American Heart Association scientific sessions 2013
  • Place of Presentation: Dallas, USA
  • Year and Date: 20131115-19
• [Presentation] 体温恒常性維持におけるナルディライジンの役割 (2013)
  • Author(s): 西城さやか, 平岡 義範, 松岡 龍彦, 大野美紀子, 中村 和弘, 松村 成暢, 西 清人, 坂本二郎, 陳 博敏, 北 徹, 木村 剛, 西 英一郎
  • Organizer: 平成 25年度 温熱生理研究会
  • Place of Presentation: 岡崎
  • Year and Date: 20130905-06
• [Presentation] ナルディライジンによる心拍数制御機構(学会奨励賞受賞) (2013)
  • Author(s): 大野美紀子, 平岡義範, 松浦博, 西清人, 西城さやか, 坂本二郎, 陳博敏, 牧山武, 北徹, 木村剛, 西英一郎
  • Organizer: 第18回日本病態プロテアーゼ学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 20130816-17
• [Presentation] Nardilysin, an Activator of Ectodomain Shedding, is a Novel and Potent Biomarker for Acute Coronary Syndrome(口頭) (2013)
  • Author(s): Ohno M, Watanabe S, Hiraoka Y, Matsuoka T, Nishi K, Saijo S, Sakamoto J, Chen PM, Inoue K, Kita T, Kimura T, Nishi E
  • Organizer: 第77回日本循環器学会総会
  • Place of Presentation: 横浜
  • Year and Date: 20130315-17
• [Presentation] Nardylisin Controls Glucose Metabolism through the Regulation of Insulin Secretion(ポスター) (2013)
  • Author(s): Nishi K, Hiraoka Y, Ohno M, Matsuoka T, Saijo S, Sakamoto J, Chen PM, Kita T, Kimura T, Nishi E
  • Organizer: 第77回日本循環器学会総会
  • Place of Presentation: 横浜
  • Year and Date: 20130315-17
• [Presentation] Nardilysin promotes cancer development through activation of ectodomain shedding (2013)
  • Author(s): Nishi E
  • Organizer: 1st International Symposium on Protein Modifications in Pathogenic Dysregulation of Signaling
  • Place of Presentation: Tokyo
  • Year and Date: 20130201-02
• [Presentation] Nardilysin, an Activator of Ectodomain Shedding, is a Novel and Potent Biomarker for Acute Coronary Syndrome(English session 最優秀賞) (2013)
  • Author(s): Ohno M, Watanabe S, Hiraoka Y, Nishi K, Saijo S, Sakamoto J, Chen PM, Kita T, Nishi E, Kimura T
  • Organizer: 第115回日本循環器学会近畿地方会
  • Place of Presentation: 京都
  • Year and Date: 2013-06-15
• [Presentation] Nardilysin regulates sinus node automaticity and sympathetic nerve innervation(ワークショップ「発生生物学の最前線 : 個と全体をつなぐ新規メカニズム」 ) (2012)
  • Author(s): Ohno M, Hiraoka Y, Matsuoka T, Nishi K, Saijo S, Kita T, Kimura T, Nishi E
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡
  • Year and Date: 20121211-14
• [Presentation] Nardylisin controls glucose metabolism through the regulation of insulin secretion (2012)
  • Author(s): Nishi K, Hiraoka Y, Ohno M, Matsuoka T, Saijyo S, Sakamoto J, Chen P, Kita T, Kimura T, Nishi E
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡
  • Year and Date: 20121211-14
• [Presentation] NRDc regulates circulatory dynamics through modulating sinus node automaticity and cardiac sympathetic innervation (2012)
  • Author(s): Ohno M, Hiraoka Y, Matsuura H, Matsuoka T, Nishi K, Saijo S, Sakamoto J, Chen PM, Kita T, Kimura T, Nishi E
  • Organizer: Neuro-Vascular Wiring Symposium 2012
  • Place of Presentation: Nara
  • Year and Date: 20121112-13
• [Presentation] Nardilysin regulates adaptive thermogenesis via modulation of transcriptional coactivator PGC-1a (Selected for oral presentation) (2012)
  • Author(s): Nishi E, Hiraoka Y, Matsuoka T, Ohno M, Nishi K, Saijo S, Kita T, Kimura T
  • Organizer: Cold Spring Harbor Meeting (Nuclear Receptors & Diseases)
  • Place of Presentation: Cold Spring Harbor, NY, USA
  • Year and Date: 20121030-1103
• [Presentation] Nardilysin, an activator of ectodomain shedding, is a novel and potent biomarker for acute coronary syndrome口頭発表 (2012)
  • Author(s): Ohno M, Watanabe S, Hiraoka Y, Matsuoka T, Nishi K, Saijo S, Kita T, Nishi E, Kimura T
  • Organizer: ESC Congress 2012
  • Place of Presentation: Munich Germany
  • Year and Date: 20120825-29
• [Presentation] NRDc regulates circulatory dynamics through modulating sinus node automaticity and cardiac sympathetic innervationポスター発表 (2012)
  • Author(s): Ohno M, Hiraoka Y, Matsuoka T, Nishi K, Saijo S, Kita T, Kimura T, Nishi E
  • Organizer: ESC Congress 2012
  • Place of Presentation: Munich Germany
  • Year and Date: 20120825-29
• [Presentation] ナルディライジンはインスリン分泌調節を介して糖代謝を制御する(学会奨励賞受賞) (2012)
  • Author(s): 西清人, 平岡義範, 大野美紀子, 松岡龍彦, 西城さやか, 坂本二郎, 陳博敏, 北徹, 木村剛, 西英一郎
  • Organizer: 第17回日本病態プロテアーゼ学会学術集会
  • Place of Presentation: 浜松
  • Year and Date: 20120810-11
• [Presentation] Nardilysin regulates circulatory dynamics through modulating sympathetic nerve innervatio (2012)
  • Author(s): Ohno M, Hiraoka Y, Matsuoka T, Nishi K, Saijo S, Kita T, Kimura T, Nishi E
  • Organizer: 第76回日本循環器学会総会
  • Place of Presentation: 福岡
  • Year and Date: 20120316-18
• [Presentation] Nardilysin regulates the mammalian circadian clock via modulating PER2 stability (2012)
  • Author(s): Hiraoka Y, Yoshitane H, Nunokawa R, Fukada Y, Kimura T and Nishi E
  • Organizer: ASCB (American Society for Cell Biology)
  • Place of Presentation: San Francisco, USA
  • Year and Date: 2012-12-15
• [Presentation] ナルディライジンは TNF-αのシェディングを促進し, マウス腸腫瘍を増大させる (口演) (2012)
  • Author(s): 神田啓太郎, 妹尾浩, 千葉勉, 西英一郎
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
  • Year and Date: 2012-09-19
• [Presentation] Critical roles of a metalloendopeputidase nardilysin in cold-induced adaptive thermogenesis. 口頭およびポスター発表 (2011)
  • Author(s): Hiraoka Y, Matsuoka T, Ohno M, Nishi K, Saijo S, Kimura T, Kita T, Nishi E
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 20111213-16
• [Presentation] Nardilysin prevents amyloid plaque formation by enhancing □-secretase activity in vivo. 口頭およびポスター発表 (2011)
  • Author(s): Ohno M, Hiraoka Y, Matsuoka T, Nishi K, Saijo S, Kimura T, Nishi E
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 20111213-16
• [Presentation] Nardilysin regulates axonal maturation and myelination in the central and peripheral nervous system (2011)
  • Author(s): Nishi E
  • Organizer: 10th Biennial ISN Satellite Meeting on Myelin Biology
  • Place of Presentation: Kolymvari, Crete, Grace
  • Year and Date: 20110824-27
  • Invited
• [Presentation] Demyelination and remyelination are distinctly regulated by nardilysin in the murine cuprizone model. Poster presentation (2011)
  • Author(s): Ohno M, Nishi E
  • Organizer: 10th Biennial ISN Satellite Meeting on Myelin Biology
  • Place of Presentation: Kolymvari, Crete, Grace
  • Year and Date: 20110824-27
• [Presentation] Nardilysin prevents amyloid plaque formation by enhancing□□-secretase activity in vivo (2011)
  • Author(s): Ohno M, Hiraoka Y, Matsuoka T, Nishi K, Saijo S, Kimura T, and Nishi E
  • Organizer: AAICAD (Alzheimer's Association International Conference on Alzheimer's Disease) 2011
  • Place of Presentation: Paris, France
  • Year and Date: 20110716-21
• [Presentation] Multiple pathophysiological roles of nardilysin, an enhancer of ectodomain shedding (2011)
  • Author(s): Nishi E
  • Organizer: Gordon Research Conference (Regulated Proteolysis of Cell Surface Proteins)
  • Place of Presentation: Davidson, NC, USA
  • Year and Date: 20110710-15
  • Invited
• [Presentation] Nardilysin regulates circulatory dynamics through modulating sympathetic nerve innervation (2011)
  • Author(s): Ohno TM, Hiraoka Y, Matsuoka T, Nishi K, Saijo S, Kimura T, and Nishi E
  • Organizer: The 84th Scientific Sessions of American Heart Association
  • Place of Presentation: Orland, Florida
  • Year and Date: 2011-11-16
• [Presentation] ナルディライジンは TNF-αのシェディングを促進し内因性サイトカインシグナル経路を活性化して胃癌細胞の増殖を制御する(口演) (2011)
  • Author(s): 神田啓太郎, 米門秀行, 妹尾浩, 千葉勉, 西英一郎
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-03
• [Book] がん基盤生物学 - 革新的シーズ育成に向けて- ,第II部 10 章細胞外ドメインシェディング活性化因子を標的とする抗がん療法 (2013)
  • Author(s): 西 英一郎
  • Publisher: 南山堂
• [Book] The Handbook of Proteolytic Enzymes (The 3 rd Edition)(Edited by Neil D. Rawlings and Guy Salvesen) (2012)
  • Author(s): Nishi E Nardilysin
  • Total Pages: 328
  • Publisher: Academic Press
• [Book] 健康長寿大事典ーEBM から QOL までー,III部 4 章 e) 深部静脈血栓症 (2012)
  • Author(s): 西城さやか, 西 英一郎
  • Publisher: 西村書店
• [Book] 心臓血管外科 Knack & Pitfalls,冠動脈外科の要点と盲点(第2版)III. 冠疾患診断の Knack & Pitfalls, 3. 冠動脈病変の重症度分類 (2012)
  • Author(s): 古川裕, 西英一郎
  • Publisher: 文光堂