Dysfunction of proteasome and pathogenesis in age-related disorders

• Project/Area Number: 25460489
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Hokkaido University
• Principal Investigator: Tomaru Utano 北海道大学, 医学(系)研究科(研究院), 准教授 (20360901)
• Co-Investigator(Kenkyū-buntansha): ISHIZU AKIHIRO 北海道大学, 大学院保健科学研究院, 教授 (60321957)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: プロテアソーム / 老化 / 老化関連疾患 / 細胞ストレス / 肺気腫 / COPD / 脳機能

Outline of Final Research Achievements

The proteasome plays a critical role in proteostasis by rapidly destroying misfolded and modified proteins generated by cellular stresses. Proteasome activity decreases with aging in many organs, and an age-related decline in proteasomal function has been implicated in various age-related pathologies. Recently, we have established a transgenic (Tg) mouse model with decreased proteasomal chymotrypsin-like activity, showing age-related phenotypes. Using this model, we demonstrate here that decreased proteasomal function accelerates cigarette smoke (CS)-induced pulmonary emphysema. CS-exposed Tg mice showed remarkable airspace enlargement and increased foci of inflammation compared with wild-type controls. Collective evidence suggests that CS exposure and impaired proteasomal activity coordinately enhance apoptotic cell death in the alveolar walls that may be involved in the development and progression of emphysema in susceptible individuals such as the elderly.

Research Products

• [Journal Article] The responses of macrophages in interaction with neutrophils that undergo NETosis (2016)
  • Author(s): Nakazawa D, Shida H, Kusunoki Y, Miyoshi A, Nishio S, Tomaru U, Atsumi T, Ishizu A
  • Journal Title: J Autoimmun Volume: Feb;67 Pages: 19-28
  • DOI: 10.1016/j.jaut.2015.08.018
  • NAID: 120005743065
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Novel monoclonal antibodies that recognize both rat and mouse phosphatidylserine/prothrombin complexes. (2016)
  • Author(s): Kawakami T, Yoon SY, Takeuchi S, Soma Y, Kuroha S, Yoshida S, Shida H, Nakazawa D, Tomaru U, Ishizu A.
  • Journal Title: Mod Rheumatol. Volume: 26(3) Issue: 3 Pages: 470-471
  • DOI: 10.3109/14397595.2015.1054090
  • NAID: 120006219908
  • Peer Reviewed
• [Journal Article] Expression of Fucosyltransferase 8 Is Associated with an Unfavorable Clinical Outcome in Non-Small Cell Lung Cancers (2015)
  • Author(s): Honma R, Kinoshita I, Miyoshi E, Tomaru U, Matsuno Y, Shimizu Y, Takeuchi S, Kobayashi Y, Kaga K, Taniguchi N, Dosaka-Akita H
  • Journal Title: Oncology Volume: 88 Issue: 5 Pages: 298-305
  • DOI: 10.1159/000369495
  • Peer Reviewed
• [Journal Article] Presence of autoimmune regulator and absence of desmoglein 1 in thymoma associated with a pemphigus foliaceus patient. (2015)
  • Author(s): Tsuchisaka, A.
  • Journal Title: Br. J. Dermatol. Volume: 印刷中 Issue: 1 Pages: 268-271
  • DOI: 10.1111/bjd.13617
  • Peer Reviewed
• [Journal Article] Decreased expression of thymus-specific proteasome subunit β5t in Down syndrome patients. (2015)
  • Author(s): Tomaru U, Tsuji T, Kiuchi S, Ishizu A, Suzuki A, Otsuka N, Ito T, Ikeda H, Fukasawa Y, Kasahara M.
  • Journal Title: Histopathology. Volume: なし Issue: 2 Pages: 235-244
  • DOI: 10.1111/his.12642
  • Peer Reviewed
• [Journal Article] The Impact of c-Fos/Activator Protein-1 Inhibition on Allogeneic Pancreatic Islet Transplantation. (2015)
  • Author(s): Yoshida T, Yamashita K, Watanabe M, Koshizuka Y, Kuraya D, Ogura M, Asahi Y, Ono H, Emoto S, Mizukami T, Kobayashi N, Shibasaki S, Tomaru U, Kamachi H, Matsushita M, Shiozawa S, Hirono S, Todo S.
  • Journal Title: Am J Transplant. Volume: 15(10) Issue: 10 Pages: 2565-2575
  • DOI: 10.1111/ajt.13338
  • Peer Reviewed / Open Access
• [Journal Article] Fatal cardiac small-vessel involvement in ANCA-associated vasculitis: an autopsy case report. (2015)
  • Author(s): Iwasaki S, Suzuki A, Fujisawa T, Sato T, Shirai S, Kamigaki M, Otsuka N, Tomaru U, Ishizu A.
  • Journal Title: Cardiovasc Pathol. Volume: 24(6) Issue: 6 Pages: 408-410
  • DOI: 10.1016/j.carpath.2015.07.005
  • NAID: 120005905594
  • Peer Reviewed
• [Journal Article] Establishment of a vascular endothelial cell-reactive type II NKT cell clone from a rat model of autoimmune vasculitis. (2015)
  • Author(s): Iinuma C, Waki M, Kawakami A, Yamaguchi M, Tomaru U, Sasaki N, Masuda S, Matsui Y, Iwasaki S, Baba T, Kasahara M, Yoshiki T, Paletta D, Herrmann T, Ishizu A.
  • Journal Title: Int Immunol. Volume: 27 Issue: 2 Pages: 105-114
  • DOI: 10.1093/intimm/dxu088
  • Peer Reviewed
• [Journal Article] Expression of Fucosyltransferase 8 Is Associated with an Unfavorable Clinical Outcome in Non-Small Cell Lung Cancers. (2015)
  • Author(s): Honma R, Kinoshita I, Miyoshi E, Tomaru U, Matsuno Y, Shimizu Y, Takeuchi S, Kobayashi Y, Kaga K, Taniguchi N, Dosaka-Akita H.
  • Journal Title: Oncology. Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Decreased proteasomal function accelerates cigarette smoke-induced pulmonary emphysema in mice (2015)
  • Author(s): Yamada Y, Tomaru U, Ishizu A, Ito T, Kiuchi T, Ono A, Miyajima S, Nagai K, HIgashi T, Matsuno Y, Dosaka-Akita H, Nishimura M, MIwa S, Kasahara M.
  • Journal Title: Lab Invest. Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Ag and IL-2 immune complexes efficiently expand Ag-specific Treg cells that migrate in response to chemokines and reduce localized immune responses. (2014)
  • Author(s): Hamano R, Baba T, Sasaki S, Tomaru U, Ishizu A, Kawano M, Yamagishi M, Mukaida N
  • Journal Title: Eur J Immunol Volume: 44 Issue: 4 Pages: 1005-1015
  • DOI: 10.1002/eji.201343434
  • Peer Reviewed / Open Access
• [Journal Article] Enhanced formation and disordered regulation of NETs in MPO-ANCA-associated microscopic polyangiitis (2014)
  • Author(s): Nakazawa D, Shida H, Tomaru U, Yoshida M, Nishio S, Atsumi T, Ishizu A.
  • Journal Title: Journal of the American Society of Nephrology Volume: Epub Issue: 5 Pages: 990-997
  • DOI: 10.1681/asn.2013060606
  • Peer Reviewed / Open Access
• [Journal Article] HTLV-1 induces a Th1-like state in CD4+CCR4+ T cells. (2014)
  • Author(s): Araya N, Sato T, Ando H, Tomaru U, Yoshida M, Coler-Reilly A, Yagishita N, Yamauchi J, Hasegawa A, Kannagi M, Hasegawa Y, Takahashi K, Kunitomo Y, Tanaka Y, Nakajima T, Nishioka K, Utsunomiya A, Jacobson S, Yamano Y.
  • Journal Title: J Clin Invest. Volume: 124 Issue: 8 Pages: 3431-42
  • DOI: 10.1172/jci75250
  • Peer Reviewed / Open Access
• [Journal Article] Decreased proteasomal activity causes photoreceptor degeneration in mice. (2014)
  • Author(s): Ando R, Noda K, Tomaru U, Kamoshita M, Ozawa Y, Notomi S, Hisatomi T, Noda M, Kanda A, Ishibashi T, Kasahara M, Ishida S.
  • Journal Title: Invest Ophthalmol Vis Sci. Volume: 55 Issue: 7 Pages: 4682-4690
  • DOI: 10.1167/iovs.13-13272
  • Peer Reviewed / Open Access
• [Journal Article] Overexpression of TNF-α converting enzyme promotes adipose tissue inflammation and fibrosis induced by high fat diet. (2014)
  • Author(s): Matsui Y, Tomaru U, Miyoshi A, Ito T, Fukaya S, Miyoshi H, Atsumi T, Ishizu A.
  • Journal Title: Exp Mol Pathol. Volume: 97(3) Issue: 3 Pages: 354-358
  • DOI: 10.1016/j.yexmp.2014.09.017
  • NAID: 120005476093
  • Peer Reviewed
• [Journal Article] Corticomedullary differentiation and maturational arrest in thymomas. (2014)
  • Author(s): Storbel P, Hartmann E, Rosenwald A, Kalla J, Ott G, Schalke B, Kasahara M, Tomaru U, Marx A.
  • Journal Title: Histopathology Volume: 64 Issue: 4 Pages: 557-566
  • DOI: 10.1111/his.12279
  • Peer Reviewed
• [Journal Article] Serum level of soluble triggering receptor expressed on myeloid cells-1 as a biomarker of disease activity in relapsing polychondritis. (2014)
  • Author(s): Sato T, Yamano Y, Tomaru U, Shimizu Y, Ando H, Okazaki T, Nagafuchi H, Shimizu J, Ozaki S, Miyazawa T, Yudoh K, Oka H, Suzuki N.
  • Journal Title: Mod Rheumatol Volume: 24(1) Issue: 1 Pages: 129-136
  • DOI: 10.3109/14397595.2013.852854
  • Peer Reviewed
• [Journal Article] Expression of thymoproteasome subunit β5t in type AB thymoma. (2014)
  • Author(s): Yamada Y, Tomaru U, Ishizu A, Kiuchi T, Kasahara M, Matsuno Y.
  • Journal Title: J Clin Pathol. Volume: 67 Issue: 3 Pages: 276-278
  • DOI: 10.1136/jclinpath-2013-201930
  • Peer Reviewed
• [Journal Article] Possible linkage between microscopic polyangiitis and thrombosis via neutrophil extracellular traps. (2014)
  • Author(s): Imamoto T, Nakazawa D, Shida H, Suzuki A, Otsuka N, Tomaru U, Ishizu A.
  • Journal Title: Clin Exp Rheumatol Volume: 32(1) Pages: 149-150
  • NAID: 120005397871
  • Peer Reviewed
• [Journal Article] Protective roles of epithelial cells in the survival of adult T-cell leukemia/lymphoma cells. (2013)
  • Author(s): Miyatake Yukiko
  • Journal Title: The American Journal of Pathology Volume: 182 Issue: 5 Pages: 1832-1842
  • DOI: 10.1016/j.ajpath.2013.01.015
  • Peer Reviewed
• [Journal Article] Thymoproteasome: roles in thymic selection and clinical applications as a diagnostic marker of thymic epithelial tumors. (2013)
  • Author(s): Tomaru, U.
  • Journal Title: Arch. Immunol. Ther. Exp. Volume: 61 Issue: 5 Pages: 357-365
  • DOI: 10.1007/s00005-013-0234-1
  • Peer Reviewed
• [Journal Article] Human papillomavirus 16-positive uterine cervical squamous cell carcinoma with coinfection with human papillomavirus 34 has a lower incidence in lymph node metastasis than that without coinfection with human papillomavirus 34. (2013)
  • Author(s): Michimata R, Watari H, Tomaru U, Sakuragi N, Ishizu A.
  • Journal Title: Pathobiology Volume: 80(5) Issue: 5 Pages: 259-264
  • DOI: 10.1159/000350423
  • NAID: 120005311820
  • Peer Reviewed
• [Journal Article] Prediction of response to treatment by gene expression profiling of peripheral blood in patients with microscopic polyangiitis. (2013)
  • Author(s): Ishizu A, Tomaru U, Murai T, Yamamoto T, Atsumi T, Yoshiki T, Yumura W, Yamagata K, Yamada H, Kumagai S, Kurokawa MS, Suka M, Makino H, Ozaki S.
  • Journal Title: PLOS ONE Volume: 8 Issue: 5 Pages: e63182-e63182
  • DOI: 10.1371/journal.pone.0063182
  • Peer Reviewed
• [Journal Article] Lysosomal-associated membrane protein-2 plays an important role in the pathogenesis of primary cutaneous vasculitis. (2013)
  • Author(s): Takeuchi S, Kimura S, Soma Y, Waki M, Yamaguchi M, Nakazawa D, Tomaru U, Ishizu A, Kawakami T
  • Journal Title: Rheumatology Volume: 52 Issue: 9 Pages: 1592-1598
  • DOI: 10.1093/rheumatology/ket159
  • Peer Reviewed
• [Journal Article] Positive feedback loop via astrocytes causes chronic inflammation in virus-associated myelopathy. (2013)
  • Author(s): Ando H., Sato T., Tomaru U., Yoshida M., Utsunomiya A., Yamauchi J., Araya N., Yagishita N., Coler-Reilly A., Shimizu Y., Yudoh K., Hasegawa Y., Nishioka K., Nakajima T., Jacobson S., Yamano Y.
  • Journal Title: Brain Volume: 136(Pt9) Issue: 9 Pages: 2876-2887
  • DOI: 10.1093/brain/awt183
  • Peer Reviewed
• [Journal Article] Possible implication of Fcγ receptor-mediated trogocytosis in susceptibility to systemic autoimmune disease. (2013)
  • Author(s): Masuda S, Iwasaki S, Tomaru U, Baba T, Katsumata K, Ishizu A
  • Journal Title: Clin Dev Immunol Volume: 2013 Pages: 345745-345745
  • DOI: 10.1155/2013/345745
  • Peer Reviewed
• [Presentation] Aberrant expression of proteasomes affects thymic T cell selection． (2015)
  • Author(s): Syota Miyajima, Utano Tomaru，Akihiro Ishizu, Shizuka Kiuchi，Masanori Kasahara．
  • Organizer: 第44回日本免疫学会総会・学術集会
  • Place of Presentation: 札幌コンベンションセンター（北海道・札幌市）
  • Year and Date: 2015-11-18
• [Presentation] 胸腺T細胞選択におけるプロテアソームキモトリプシン様活性サブユニットの役割． (2015)
  • Author(s): 宮島祥太，外丸詩野，石津明洋，木内静香，大井智貴，笠原正典．
  • Organizer: 第104回日本病理学会総会
  • Place of Presentation: 名古屋国際会議場（愛知県・名古屋市）
  • Year and Date: 2015-04-30
• [Presentation] プロテアソーム機能低下マウスにおける記銘力障害の解析． (2015)
  • Author(s): 伊藤智樹，外丸詩野，大村優，戸松留花，石津明洋，笠原正典．
  • Organizer: 第104回日本病理学会総会
  • Place of Presentation: 名古屋国際会議場（愛知県・名古屋市）
  • Year and Date: 2015-04-30
• [Presentation] ダウン症患者の胸腺におけるプロテアソームサブユニットβ5tの発現低下． (2015)
  • Author(s): 木内静香，外丸詩野，辻隆裕，石津明洋，鈴木昭，大塚紀幸，伊藤智樹，池田仁，深澤雄一郎，笠原正典．
  • Organizer: 第104回日本病理学会総会
  • Place of Presentation: 名古屋国際会議場（愛知県・名古屋市）
  • Year and Date: 2015-04-30
• [Presentation] Type B胸腺腫、胸腺癌におけるカテプシンの発現． (2015)
  • Author(s): 安部樹太朗，有賀茜，外丸詩野，木内静香，石津明洋，大塚紀幸，清水知浩，丸川活司，松野吉宏，笠原正典．
  • Organizer: 第104回日本病理学会総会
  • Place of Presentation: 名古屋国際会議場（愛知県・名古屋市）
  • Year and Date: 2015-04-30
• [Presentation] 壁在結節を伴う卵巣粘液産生腺癌の3例． (2015)
  • Author(s): 河内麻里亜，横山達也，大塚紀幸，藤本俊郎，池田仁，高木芳武，石津明洋，外丸詩野，笠原正典．
  • Organizer: 第104回日本病理学会総会
  • Place of Presentation: 名古屋国際会議場（愛知県・名古屋市）
  • Year and Date: 2015-04-30
• [Presentation] ダウン症患者の胸腺におけるプロテアソームサブユニットβ5tの発現低下. (2015)
  • Author(s): 木内静香、外丸詩野、辻 隆裕、石津明洋、鈴木 昭、大塚紀幸、伊藤智樹、池田 仁、深澤雄一郎、笠原正典
  • Organizer: 第34回日本胸腺研究会
  • Place of Presentation: ユニコムプラザさがみはら（神奈川県・相模原市）
  • Year and Date: 2015-02-07
• [Presentation] Aberrant expression of proteasomal β5 subunit affects T cell repertoires in the thymus. (2014)
  • Author(s): Shizuka Kiuchi，Utano Tomaru，Saori Konno，Shota Miyajima，Akihiro Ishizu，Masanori Kasahara
  • Organizer: 第43回日本免疫学会総会・学術集会
  • Place of Presentation: 国立京都国際会館（京都府・京都市）
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] 高血糖による好中球細胞トラップ（neutrophil extracellular traps：NETｓ）の形成亢進 (2014)
  • Author(s): 三次有奈、山田真衣、舘山ゆう、楠由宏、志田玄貴、中沢大悟、外丸詩野、三好秀明、渥美達也、石津明洋
  • Organizer: 第47回北海道病理談話会（病理分科会）
  • Place of Presentation: 旭川グランドホテル（北海道・旭川市）
  • Year and Date: 2014-10-11
• [Presentation] 抗ラクトフェリン抗体の病原性 (2014)
  • Author(s): 志田玄貴、中沢大悟、舘山ゆう、山田真衣、楠由宏、三次有奈、外丸詩野、渥美達也、石津明洋
  • Organizer: 第47回北海道病理談話会（病理分科会）
  • Place of Presentation: 旭川グランドホテル（北海道・旭川市）
  • Year and Date: 2014-10-11
• [Presentation] プロテアソーム機能低下モデルマウスにおける脳機能障害の解析. (2014)
  • Author(s): 伊藤智樹，外丸詩野，大村優， 戸松留花，石津明洋，笠原正典
  • Organizer: 第47回北海道病理談話会（病理分科会）
  • Place of Presentation: 旭川グランドホテル（北海道・旭川市）
  • Year and Date: 2014-10-11
• [Presentation] 胸腺におけるプロテアソームキモトリプシン様活性サブユニットの発現とT細胞選択. (2014)
  • Author(s): 木内静香、外丸詩野、紺野沙織、石津明洋、宮島祥太、平川彩香、笠原正典
  • Organizer: 第103回日本病理学会総会
  • Place of Presentation: ANAクラウンプラザ（広島県・広島市）
  • Year and Date: 2014-04-24 – 2014-04-26
• [Presentation] プロテアソーム機能異常と脳機能の低下 (2014)
  • Author(s): 伊藤智樹、外丸詩野、大村優、石津明洋、笠原正典
  • Organizer: 第103回日本病理学会総会
  • Place of Presentation: ANAクラウンプラザ（広島県・広島市）
  • Year and Date: 2014-04-24 – 2014-04-26
• [Presentation] 高齢男性でみられたEBV陽性肝脾γδT細胞リンパ腫の一例. (2014)
  • Author(s): 竹中淳規、大塚紀幸、藤田裕美、中馬誠、外丸詩野、石津明洋、笠原正典
  • Organizer: 第103回日本病理学会総会
  • Place of Presentation: ANAクラウンプラザ（広島県・広島市）
  • Year and Date: 2014-04-24 – 2014-04-26
• [Presentation] プロテアソームの機能異常と病態 (2013)
  • Author(s): 外丸詩野
  • Organizer: 第102回日本病理学会総会
  • Place of Presentation: ロイトン札幌（札幌）
• [Presentation] プロテアソームの発現異常における免疫応答の変化 (2013)
  • Author(s): 紺野沙織、外丸詩野、岸本栞奈、石津明洋、笠原正典
  • Organizer: 第102回日本病理学会総会
  • Place of Presentation: ロイトン札幌（札幌）
• [Presentation] プロテアソームの機能異常と病理作用 (2013)
  • Author(s): 外丸詩野
  • Organizer: 第59回日本病理学会秋期特別総会
  • Place of Presentation: 甲府富士屋ホテル（甲府）
• [Presentation] Aberrant proteasomal expression affects T cell differentiation and functions. (2013)
  • Author(s): Konno S, Tomaru U, Ishizu A, Kasahara M
  • Organizer: 第42回日本免疫学会学術集会
  • Place of Presentation: 幕張メッセ（千葉）
• [Remarks] 北海道大学医学研究科 病理学講座 分子病理学分野 ホームページ
  • URL: http://path1.med.hokudai.ac.jp/path1/index.html
• [Remarks] 北海道大学大学院 医学研究科 分子病理学分野HP
  • URL: http://www.path1-hokudai.jp/path1/
• [Remarks] 北海道大学大学院 医学研究科 病理学講座 分子病理学分野HP
  • URL: http://www.path1-hokudai.jp/path1/Welcome.html