Development of liquid biopsy against dementia

• Project/Area Number: 15K15100
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Human pathology
• Research Institution: Tokyo Medical University
• Principal Investigator: Kuroda Masahiko 東京医科大学, 医学部, 主任教授 (80251304)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: Dementia / Alzheimer's disease / microRNA / liquid biopsy / exosome / 血清miRNA / エクソソーム / 内部標準物質 / 認知症 / リキッドバイオプシー

Outline of Final Research Achievements

Dementia is of one the intractable disease that is characterize neurodegeneration. And the number of patients of Alzheimer's disease(AD) is rapidly growing in world wide. Problematic point of AD, the etiology of the is still poorly understood. In addition, we do not have early detection marker of AD and effective drug against AD. MicroRNAs are a family of 19- to 25-nucleotides noncoding small RNAs that primarily function as gene regulators. Aberrant microRNA expression has been observed human disease including human malignancies. Despite this knowledge, there is little information regarding microRNAs in plasma AD patient. In this project, we focused circulating miRNA in AD and whether expression levels of specific microRNAs differ between AD and healthy individuals. And we found some miRNA of plasma was highly expressed in AD patient. These miRNAs have strong potential for clinical application as a novel biomarker for detection of AD.

Research Products

• [Journal Article] Vascular Smooth Muscle Cell Maturation Stage and Ki-67 Index are Diagnostic Biomarkers for Pathologic Grade of Ovarian Teratoma. (2017)
  • Author(s): Hongo-Kohama M, Kurata A, Hashimoto H, Fujita K, Horiuchi H, Nagao T, Kuroda M.
  • Journal Title: Int J Gynecol Pathol. Volume: ahead of print Issue: 6 Pages: 582-592
  • DOI: 10.1097/pgp.0000000000000373
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Repression of Smad3 by Stat3 and c-Ski/SnoN induces gefitinib resistance in lung adenocarcinoma. (2017)
  • Author(s): Makino Y, Yoon JH, Bae E, Kato M, Miyazawa K, Ohira T, Ikeda N, Kuroda M, Mamura M.
  • Journal Title: Biochem Biophys Res Commun. Volume: 484 Issue: 2 Pages: 269-77
  • DOI: 10.1016/j.bbrc.2017.01.093
  • NAID: 120007134941
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Novel form of miR-29b suppresses bleomycin-induced pulmonary fibrosis. (2017)
  • Author(s): Yamada Y, Takanashi M, Sudo K, Ueda S, Ohno SI, Kuroda M.
  • Journal Title: PLoS One. Volume: 12 Issue: 2 Pages: 0171957-0171957
  • DOI: 10.1371/journal.pone.0171957
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cardiac myofibroblast engulfment of dead cells facilitates recovery after myocardial infarction. (2017)
  • Author(s): Michio Nakaya,Kenji Watari,Mitsuru Tajima,Takeo Nakaya,Shoichi Matsuda,Hiroki Ohara,Hiroaki Nishihara,Hiroshi Yamaguchi,Akiko Hashimoto,Mitsuho Nishida,Akiomi Nagasaka,Yuma Horii,Hiroki Ono,Gentaro Iribe,Ryuji Inoue,Makoto Tsuda,Kazuhide Inoue,Akira Tanaka,Masahiko Kuroda,Shigekazu Nagata,Hitoshi Kurose
  • Journal Title: Journal of Clinical Investigation Volume: 127 Issue: 1 Pages: 383-401
  • DOI: 10.1172/jci83822
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] MiR-29a Assists in Preventing the Activation of Human Stellate Cells and Promotes Recovery From Liver Fibrosis in Mice. (2016)
  • Author(s): Matsumoto Y, Itami S, Kuroda M, Yoshizato K, Kawada N, Murakami Y.
  • Journal Title: Mol Ther. Volume: 24 Issue: 10 Pages: 1848-59
  • DOI: 10.1038/mt.2016.127
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Necrotizing arteritis occurring in an intralobar pulmonary sequestration of a patient without systemic vasculitis syndrome. (2016)
  • Author(s): Hashimoto H, Hara K, Matsumoto J, Nashiro T, Nagano M, Kusakabe M, Kurata A, Kuroda M, Suzuki Y, Horiuchi H.
  • Journal Title: Cardiovasc Pathol. Volume: 25 Issue: 3 Pages: 200-2
  • DOI: 10.1016/j.carpath.2016.01.005
  • Peer Reviewed / Open Access
• [Journal Article] Development of novel small hairpin RNAs that do not require processing by dicer or AGO2 (2016)
  • Author(s): Ohno S, Itano K, Harada Y, Asada K, Oikawa K, Kashiwazako M, Okuyama H, Kumagai K, Takanashi M, Sudo K, Ikeda N, Kuroda M.
  • Journal Title: Mol Ther Volume: 24 Issue: 7 Pages: 1278-1289
  • DOI: 10.1038/mt.2016.81
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] HLA-G expression is regulated by miR-365 in trophoblasts under hypoxic conditions. (2016)
  • Author(s): Mori A, Nishi H, Sasaki T, Nagamitsu Y, Kawaguchi R, Okamoto A, Kuroda M, Isaka K.
  • Journal Title: Placenta. Volume: 45 Pages: 37-41
  • DOI: 10.1016/j.placenta.2016.07.004
  • Peer Reviewed / Open Access
• [Journal Article] Cord Blood-Derived Endothelial Colony-Forming Cell Function is Disrupted in Congenital Diaphragmatic Hernia (2016)
  • Author(s): Hideshi Fujinaga, Hiroko Fujinaga, Nobuyuki Watanabe, Tomoko Kato, Moe Tamano, Miho Terao, Shuji Takada, Yushi Ito, Akihiro Umezawa, Masahiko Kuroda
  • Journal Title: American Journal of Physiology-Lung Cellular and Molecular Physiology Volume: 310 Issue: 11 Pages: 1143-1154
  • DOI: 10.1152/ajplung.00357.2015
  • NAID: 120005845870
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Solitary Pulmonary Capillary Hemangioma of Adult Cases: Clinicopathologic Characteristics as an Unrecognized Entity. (2016)
  • Author(s): Hashimoto H, Kurata A, Fujiwara M, Hara K, Matsumoto J, Kusakabe M, Tachibana K, Nashiro T, Terado Y, Akahane M, Usui K, Suzuki Y, Kondo H, Kamma H, Kuroda M, Horiuchi H.
  • Journal Title: Am J Surg Pathol. Volume: 40 Issue: 10 Pages: 1380-1389
  • DOI: 10.1097/pas.0000000000000708
  • Peer Reviewed / Open Access
• [Journal Article] Topical Use of Angiopoietin-like Protein 2 RNAi-loaded Lipid Nanoparticles Suppresses Corneal Neovascularization. (2016)
  • Author(s): Taketani Y, Usui T, Toyono T, Shima N, Yokoo S, Kimakura M, Yamagami S, Ohno S, Onodera R, Tahara K, Takeuchi H, Kuroda M.
  • Journal Title: Mol Ther Nucleic Acids. Volume: 5 Pages: e292-e292
  • DOI: 10.1038/mtna.2016.1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] MicroRNA and gynecologic cancers. (2016)
  • Author(s): Kanekura K, Nishi H, Isaka K, Kuroda M.
  • Journal Title: J Obstet Gynaecol Res. Volume: 10.1111/jog.12995 Issue: 6 Pages: 052-052
  • DOI: 10.1111/jog.12995
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Poly-dipeptides encoded by the C9ORF72 repeats block global protein translation. (2016)
  • Author(s): Kanekura K, Yagi T, Cammack AJ, Mahadevan J, Kuroda M, Harms MB, Miller TM, Urano F.
  • Journal Title: Hum Mol Genet. Volume: ahead of print
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Focus on Extracellular Vesicles: Development of Extracellular Vesicle-Based Therapeutic Systems. (2016)
  • Author(s): Ohno S, Drummen G, Kuroda M.
  • Journal Title: Int. J. Mol. Sci. Volume: 17(2) Issue: 2 Pages: 172-191
  • DOI: 10.3390/ijms17020172
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Quantitative nucleic features are effective for discrimination of intraductal proliferative lesions of the breast. (2016)
  • Author(s): Yamada M, Saito A, Yamamoto Y, Cosatto E, Kurata A, Nagao T, Tateishi A, Kuroda M.
  • Journal Title: J Pathol Inform Volume: 7 Issue: 1 Pages: 7-7
  • DOI: 10.4103/2153-3539.175380
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Novel types of small RNA exhibit sequence- and target-dependent angiogenesis suppression without activation of Toll-like Receptor 3 in an age-related macular degeneration (AMD) mouse model. (2015)
  • Author(s): Takanashi M, Sudo K, Ueda S, Ohno S, Yamada Y, Osakabe Y, Goto H, Matsunaga Y, Ishikawa A, Usui , Kuroda M.
  • Journal Title: Mol Ther Nucleic Acids. Volume: 4 Pages: e258-e258
  • DOI: 10.1038/mtna.2015.34
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Does perineural invasion of the myenteric plexus have a key role in annular rectal invasion and digestive system symptoms of prostate carcinoma patients? (2015)
  • Author(s): Hashimoto H, Kurata A, Nashiro T, Kuroda M, Horiuchi H
  • Journal Title: Med Hypotheses Volume: 85 Issue: 6 Pages: 854-7
  • DOI: 10.1016/j.mehy.2015.09.024
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Phosphorylation status determines the opposing functions of Smad2/Smad3 as STAT3 cofactors in TH17 differentiation. (2015)
  • Author(s): Yoon JH, Sudo K, Kuroda M, Kato M, Lee IK, Han JS, Nakae S, Imamura T, Kim J, Ju JH, Kim DK, Matsuzaki K, Weinstein M, Matsumoto I, Sumida T, Mamura M
  • Journal Title: Nat Commun. Volume: 6 Issue: 1 Pages: 7600-7600
  • DOI: 10.1038/ncomms8600
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Evaluation of the Human Papillomavirus mRNA Test for the detection of cervical lesions in Japan. (2015)
  • Author(s): Nakayama Y, Yamada M, Kurata A, Kiseki H, Kuroda M.
  • Journal Title: Eur J Gynaec Oncol Volume: 36 Pages: 192-6
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Ovarian small cell carcinoma of pulmonary type appearing in ante-mortem ascites: An autopsy case and review of the literature (2015)
  • Author(s): Hirotsugu Hashimoto, Atsushi Kurata, Koji Fujita, Hideto Shimada, Takeshi Nagai, Hajime Horiuchi, Masahiko Kuroda
  • Journal Title: Human Pathology: Case Reports Volume: 未定 Issue: 3 Pages: 6-6
  • DOI: 10.1016/j.ehpc.2015.02.003
  • Peer Reviewed / Open Access
• [Journal Article] Inhibition of choroidal fibrovascular membrane formation by new class of RNA interference therapeutic agent targeting periostin. (2015)
  • Author(s): Nakama T, Yoshida S, Ishikawa K, Kobayashi Y, Zhou Y, Nakao S, Sassa Y, Oshima Y, Takao K, Shimahara A, Yoshikawa K, Hamasaki T, Ohgi T, Hayashi H, Matsuda A, Kudo A, Nozaki M, Ogura Y, Kuroda M, Ishibashi T.
  • Journal Title: Gene Therapy. Volume: 22 Issue: 2 Pages: 127-137
  • DOI: 10.1038/gt.2014.112
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Angiopoietin-like 7 is an anti-angiogenic protein required to prevent vascularization of the cornea. (2015)
  • Author(s): Toyono T, Usui T, Yokoo S, Taketani Y, Nakagawa S, Kuroda M, Yamagami S, Amano S.
  • Journal Title: PLoS One Volume: 10 Issue: 1 Pages: e0116838-e0116838
  • DOI: 10.1371/journal.pone.0116838
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Immaturity of smooth muscle cells in the neointima is associated with acute coronary syndrome. (2015)
  • Author(s): Horita A, Kurata A, Ohno S, Shimoyamada H, Saito I, Kamma H, Kuroda M.
  • Journal Title: Cardiovasc Pathol Volume: 24 Issue: 1 Pages: 26-32
  • DOI: 10.1016/j.carpath.2014.09.003
  • Peer Reviewed / Open Access
• [Presentation] Digital Pethologyを用いた肝細胞がんの形態学解析による再発予測の検討. (2017)
  • Author(s): 齋藤 彰、藤田浩司、山本陽一郎、硲 彰一、坂本和彦、永野浩昭、黒田雅彦.
  • Organizer: 第106回日本病理学会総会
  • Place of Presentation: 京王プラザホテル(東京)
  • Year and Date: 2017-04-27
• [Presentation] 子宮頸部上皮内腫瘍病変に対する新規モノクロナール抗体の開発. (2017)
  • Author(s): 藤田浩司、大野慎一郎、西 洋孝、井坂恵一、黒田雅彦.
  • Organizer: 第106回日本病理学会総会
  • Place of Presentation: 京王プラザホテル(東京)
  • Year and Date: 2017-04-27
• [Presentation] Activation of TLR2 regulates CARD10 gene expression by miR-146a-5p in oral squamous cell carcinoma. (2017)
  • Author(s): 池畑直樹、高梨正勝、上田しのぶ、里見貴史、渡辺正人、長谷川温、河野通秀、榎本 愛、黒田雅彦、近津大地.
  • Organizer: 第106回日本病理学会総会
  • Place of Presentation: 京王プラザホテル(東京)
  • Year and Date: 2017-04-27
• [Presentation] RNA干渉核酸に働く短鎖ヘアピンRNAの探索と機能解析. (2017)
  • Author(s): 大野慎一郎、原田裕一郎、村上善基、黒田雅彦.
  • Organizer: 第106回日本病理学会総会
  • Place of Presentation: 京王プラザホテル(東京)
  • Year and Date: 2017-04-27
• [Presentation] miRNA生成経路を欠損する肺がん細胞株の解析. (2017)
  • Author(s): 老川桂生、淺田浩太朗、大野慎一郎、黒田雅彦.
  • Organizer: 第106回日本病理学会総会
  • Place of Presentation: 京王プラザホテル(東京)
  • Year and Date: 2017-04-27
• [Presentation] Clinicopathogic Characteristics of solitary pulmonary capillary hemangioma. (2017)
  • Author(s): 橋本浩次、倉田 厚、藤原正親、原 啓、名城珠希、増田芳雄、鈴木良夫、菅間 博、黒田雅彦、堀内 啓.
  • Organizer: 第106回日本病理学会総会
  • Place of Presentation: 京王プラザホテル(東京)
  • Year and Date: 2017-04-27
• [Presentation] 浸潤性乳管癌に出現するlet-7発現細胞の検討. (2017)
  • Author(s): 鶴井敏光、藤田浩司、大野慎一郎、黒田雅彦.
  • Organizer: 第106回日本病理学会総会
  • Place of Presentation: 京王プラザホテル(東京)
  • Year and Date: 2017-04-27
• [Presentation] Mir-34aによるがん抑制遺伝子BLUの発現制御機構. (2017)
  • Author(s): 三部芳裕、大野慎一郎、黒田雅彦.
  • Organizer: 第106回日本病理学会総会
  • Place of Presentation: 京王プラザホテル(東京)
  • Year and Date: 2017-04-27
• [Presentation] RNAワールドと肺がん発がん機構 (2016)
  • Author(s): 黒田雅彦.
  • Organizer: 第108回ACCP日本部会定期教育講演会.
  • Place of Presentation: 東京医科大学病院(東京)
  • Year and Date: 2016-10-29
• [Presentation] TLS-CHOPを発現する粘液型脂肪肉腫細胞における腫瘍関連分子経路の解析. (2016)
  • Author(s): 及川恒輔、高梨正勝、佐野冬樹、黒田雅彦、村垣泰光.
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（横浜）
  • Year and Date: 2016-10-06
• [Presentation] 規ヘアピン型RNA干渉核酸の探索と機能解析. (2016)
  • Author(s): 大野慎一郎、原田裕一郎、村上善基、黒田雅彦.
  • Organizer: 第8回日本RNAi研究会、第3回日本細胞外小胞体学会
  • Place of Presentation: グランドプリンスホテル広島（広島）
  • Year and Date: 2016-08-31
• [Presentation] miRNA生成経路を欠損する肺がん細胞株の解析 (2016)
  • Author(s): 老川桂生、浅田浩太朗、大野慎一郎、黒田雅彦
  • Organizer: 第105回日本病理学会総会
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2016-05-12
• [Presentation] 肺がんにおけるArgonauteファミリーの機能解析 (2016)
  • Author(s): 大野慎一郎、浅田浩太朗、老川桂生、原田裕一郎、黒田雅彦
  • Organizer: 第105回日本病理学会総会
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2016-05-12
• [Presentation] 乳がん幹細胞の酸化ストレス抵抗性におけるmiR-27aの作用 (2016)
  • Author(s): 上田しのぶ、高梨正勝、黒田雅彦
  • Organizer: 第105回日本病理学会総会
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2016-05-12
• [Presentation] 血管炎症候群を伴わない患者の肺葉内肺分画症に見られた壊死性動脈炎 (2016)
  • Author(s): 橋本浩次、原 啓、松本 順、名城珠希、増田芳雄、長野匡晃、日下部将司、黒田雅彦、鈴木良夫、堀内 啓
  • Organizer: 第105回日本病理学会総会
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2016-05-12
• [Presentation] Development of novel Dicer- and Ago2-independent small hairpin RNAs (2016)
  • Author(s): Shin-ichiro OHNO, Karen ITANO, Yuicirou HARADA, Koutaro ASADA, Keiki OIKAWA, Mikie KASHIWAZAKO, Hikaru OKUYAMA, Katsuyoshi KUMAGAI, Masakatsu TAKANASHI, Katsuko SUDO, Norihiko IKEDA, Masahiko KURODA.
  • Organizer: American Society of Gene & Cell Therapy(ASGCT) 19th Annual Meeting. (第19回米国遺伝子治療学会)
  • Place of Presentation: Marriot Wardman Park Hotel, Washington,DC, USA
  • Year and Date: 2016-05-04
  • Int'l Joint Research
• [Presentation] エクソソームが開く新しい医療 (2015)
  • Author(s): 黒田雅彦
  • Organizer: 第19回日本統合医療学会
  • Place of Presentation: 山口市民会館（山口県山口市）
  • Year and Date: 2015-12-12
  • Invited
• [Presentation] 子宮頸部上皮腫瘍（cervical intraepithelial neoplasia; CIN）の抗MUC1抗体における染色性の検討 (2015)
  • Author(s): 藤田浩司、倉田 厚、別所泰子、峯尾松一郎、黒田雅彦
  • Organizer: 第12回日本病理学会カンファレンス
  • Place of Presentation: 六甲山ホテル（神戸市灘区）
  • Year and Date: 2015-07-24
• [Presentation] ダニ抗原で誘発させたアトピー性皮膚炎モデルマウスの作成 (2015)
  • Author(s): 柏迫幹絵、高梨正勝、黒田雅彦
  • Organizer: 第12回日本病理学会カンファレンス
  • Place of Presentation: 六甲山ホテル（神戸市灘区）
  • Year and Date: 2015-07-24
• [Presentation] 肺線維症に対するmiR-29b補充療法 (2015)
  • Author(s): 山田侑子、高梨正勝、須藤カツ子、上田しのぶ、黒田雅彦
  • Organizer: 第12回日本病理学会カンファレンス
  • Place of Presentation: 六甲山ホテル（神戸市灘区）
  • Year and Date: 2015-07-24
• [Presentation] 肺がんにおけるArgonauteﾌｧﾐﾘｰの発現・機能解析 (2015)
  • Author(s): 浅田浩太朗、老川桂生、大野慎一郎、黒田雅彦
  • Organizer: 第12回日本病理学会カンファレンス
  • Place of Presentation: 六甲山ホテル（神戸市灘区）
  • Year and Date: 2015-07-24
• [Presentation] microRNAの生成経路を欠損する肺がん細胞株の解析 (2015)
  • Author(s): 老川桂生、浅田浩太朗、大野慎一郎、黒田雅彦
  • Organizer: 第12回日本病理学会カンファレンス
  • Place of Presentation: 六甲山ホテル（神戸市灘区）
  • Year and Date: 2015-07-24
• [Presentation] 副作用を軽減した短鎖型核酸医薬の開発 (2015)
  • Author(s): 大野慎一郎、板野華蓮、浅田浩太朗、老川桂生、柏迫幹絵、高梨正勝、黒田雅彦
  • Organizer: 第12回日本病理学会カンファレンス
  • Place of Presentation: 六甲山ホテル（神戸市灘区）
  • Year and Date: 2015-07-24
• [Presentation] 計測画像情報の病理学への応用 (2015)
  • Author(s): 黒田雅彦
  • Organizer: 第12回日本病理学会カンファレンス
  • Place of Presentation: 六甲山ホテル（神戸市灘区）
  • Year and Date: 2015-07-24
  • Invited
• [Book] グリオーマ治療のDecision Making 脳神経外科診療プラクティス (2016)
  • Author(s): 上田しのぶ、黒田雅彦
  • Total Pages: 304
  • Publisher: 文光堂
• [Patent(Industrial Property Rights)] プロレニン遺伝子またはプロレニン受容体遺伝子の発現を抑制する一本鎖核酸分子およびその用途 (2016)
  • Inventor(s): 黒田雅彦
  • Industrial Property Rights Holder: 北海道大学、株式会社ボナック、東京医科大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2016-12-29
  • Overseas
• [Patent(Industrial Property Rights)] 遺伝子発現制御のための発現制御核酸分子およびその用途 (2016)
  • Inventor(s): 黒田雅彦、大野慎一郎
  • Industrial Property Rights Holder: 東京医科大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2016-168499
  • Filing Date: 2016-08-30