Establishment of new biomarkers for uveitis and development of treatments by transomics analysis

• Project/Area Number: 19K09959
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56060:Ophthalmology-related
• Research Institution: Tokyo Medical University
• Principal Investigator: Usui Yoshihiko 東京医科大学, 医学部, 准教授 (50408142)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2021: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 炎症性眼疾患 / ぶどう膜炎 / 人工知能 / 機械学習 / オミックス解析 / マイクロRNA / メタボローム / バイオマーカー

Outline of Research at the Start

ぶどう膜炎は視力障碍の主要な原因疾患の１つであるが、診断や治療効果判定に確立したバイオマーカーや治療法は未だない。本研究では、各種ヒトぶどう膜炎の臨床データおよび検体を用いて、病態をトランスオミックス解析で包括的に解明することで診断や治療効果判定におけるバイオマーカーを確立し、これらに対する新規治療法の開発も視野に入れる。その結果に基づいて候補因子をマウス実験的自己免疫性ぶどう膜炎に投与することにより、炎症が抑制できるかを個体および細胞レベルで検討することで新規病態メカニズムの解明と治療法を開発することを目的とする。

Outline of Final Research Achievements

Uveitis is one of the major causative diseases of visual impairment, but there are no established biomarkers or treatments for diagnosis and judgment of therapeutic effect. In this study, we make full use of bioinformatics and artificial intelligence to develop inflammatory eye diseases, from the results of general tests that have been performed in insurance clinics to the large amount of data obtained by the latest omics analysis. Created a new biomarker for. In particular, I was able to create new biomarkers for intraocular lymphoma, acute retinal necrosis, and endophthalmitis, which have poor visual acuity.

Academic Significance and Societal Importance of the Research Achievements

ベーチェット病やVogt-小柳-原田病などの非感染性ぶどう膜炎には疾患特異的なバイオマーカーが存在しないため、新規バイオマーカーの同定ができれば、早期診断に寄与できるのみならず、治療効果判定や再発の重要な指標となり得る。また、ぶどう膜炎との鑑別にしばしば苦慮する眼内リンパ腫では適切な診断が生命予後を左右するため、生命予後を推定することができるバイオマーカーを創出することができ、今後の個別化治療の基礎になるデータと思われる。

Research Products

• [Int'l Joint Research] スクリプス研究所(米国)
• [Int'l Joint Research] ハーバード大学(米国)
• [Journal Article] Programmed Cell Death-1 Pathway Deficiency Enhances Autoimmunity Leading to Dacryoadenitis of Mice. (2021)
  • Author(s): Sakurai Y, Usui Y, Hattori T, Takeuchi M, Takayama K, Karasawa Y, Nishio Y, Yamakawa N, Saitoh D, Goto H, Ito M.
  • Journal Title: Am J Pathol Volume: in press Issue: 6 Pages: 1077-1093
  • DOI: 10.1016/j.ajpath.2021.02.014
  • Peer Reviewed / Open Access
• [Journal Article] Optical coherence tomography angiography for the diagnosis of granulomatosis with polyangiitis with serous retinal detachment: A case report (2021)
  • Author(s): Takashi N, Nakamura A, Kataoka K, Usui Y, Ito Y, Kaneko H.
  • Journal Title: Medicine Volume: 100 Issue: 7 Pages: e24789-e24789
  • DOI: 10.1097/md.0000000000024789
  • Peer Reviewed / Open Access
• [Journal Article] Share Differential Tissue Metabolic Signatures in IgG4-Related Ophthalmic Disease and Orbital Mucosa-Associated Lymphoid Tissue Lymphoma. (2021)
  • Author(s): Shimizu H, Usui Y, Wakita R, Aita Y, Tomita A, Tsubota K, Asakage M, Nezu N, Komatsu H, Umazume K, Sugimoto M, Goto H.
  • Journal Title: Invest Ophthalmol Vis Sci Volume: in press Issue: 1 Pages: 15-15
  • DOI: 10.1167/iovs.62.1.15
  • Peer Reviewed / Open Access
• [Journal Article] Comprehensive Gene Analysis of IgG4-Related Ophthalmic Disease Using RNA Sequencing (2021)
  • Author(s): Asakage M, Usui Y, Nezu N, Shimizu H, Tsubota K, Umazume K, Yamakawa N, Umezu T, Suwanai H, Kuroda M, Goto H.
  • Journal Title: Invest Ophthalmol Vis Sci Volume: in press Issue: 11 Pages: 3548-3548
  • DOI: 10.3390/jcm9113458
  • NAID: 120007183860
  • Peer Reviewed / Open Access
• [Journal Article] Anti-TNF-α Therapy for Refractory Uveitis Associated with Behçet's Syndrome and Sarcoidosis: A Single Center Study of 131 Patients (2021)
  • Author(s): Kunimi K, Usui Y, Asakage M, Maehara C, Tsubota K, Mitsuhashi R, Umazume A, Kezuka T, Sakai JI, Goto H.
  • Journal Title: Ocul Immunol Inflamm Volume: in press Issue: 1 Pages: 223-230
  • DOI: 10.1080/09273948.2020.1791346
  • Peer Reviewed / Open Access
• [Journal Article] Vitreous metabolomics profiling of proliferative diabetic retinopathy (2021)
  • Author(s): Tomita Y, Cagnone G, Fu Z, Cakir B, Kotoda Y, Asakage M, Wakabayashi Y, Hellström A, Joyal JS, Talukdar S, Smith LEH, Usui Y.
  • Journal Title: Diabetologia Volume: 64 Issue: 1 Pages: 70-82
  • DOI: 10.1007/s00125-020-05309-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Identification of Markers Predicting Clinical Course in Patients with IgG4-Related Ophthalmic Disease by Unbiased Clustering Analysis (2020)
  • Author(s): Tsubota K, Usui Y, Nemoto R, Goto H.
  • Journal Title: J Clin Med Volume: 9 Issue: 12 Pages: 4084-4084
  • DOI: 10.3390/jcm9124084
  • Peer Reviewed / Open Access
• [Journal Article] Serum Metabolomic Profiling of Patients with Non-Infectious Uveitis. (2020)
  • Author(s): Shimizu H, Usui Y, Asakage M, Nezu N, Wakita R, Tsubota K, Sugimoto M, Goto H.
  • Journal Title: J Clin Med Volume: 9 Issue: 12 Pages: 3955-3955
  • DOI: 10.3390/jcm9123955
  • Peer Reviewed / Open Access
• [Journal Article] Blockade of costimulatory CD27/CD70 pathway promotes corneal allograft survival (2020)
  • Author(s): Narimatsu A, Hattori T, Hiroki Ueno et al
  • Journal Title: Experimental eye research Volume: 199 Pages: 108190-108190
  • DOI: 10.1016/j.exer.2020.108190
  • Peer Reviewed
• [Journal Article] Retinal microglia are critical for subretinal neovascular formation. (2020)
  • Author(s): Usui-Ouchi A, Usui Y, Kurihara T, Aguilar E, Dorrell MI, Ideguchi Y, Sakimoto S, Bravo S, Friedlander M.
  • Journal Title: JCI insight Volume: 5 Issue: 12 Pages: 1391-1391
  • DOI: 10.1172/jci.insight.137317
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Elucidation of Pathophysiology and Novel Treatment for Diabetic Macular Edema Derived from the Concept of Neurovascular Unit (2020)
  • Author(s): Usui Y
  • Journal Title: JMA J Volume: 3 Issue: 3 Pages: 201-207
  • DOI: 10.31662/jmaj.2020-0022
  • NAID: 130007905844
  • Peer Reviewed / Open Access
• [Journal Article] High-Throughput MicroRNA Profiling of Vitreoretinal Lymphoma: Vitreous and Serum MicroRNA Profiles Distinct from Uveitis. (2020)
  • Author(s): Minezaki T, Usui Y, Asakage M, Takanashi M, Shimizu H, Nezu N, Narimatsu A, Tsubota K, Umazume K, Yamakawa N, Kuroda M, Goto H.
  • Journal Title: J Clin Med. Volume: 9(6) Issue: 6 Pages: 1844-1844
  • DOI: 10.3390/jcm9061844
  • Peer Reviewed / Open Access
• [Journal Article] Changes in Etiology of Uveitis in a Single Center in Japan. (2020)
  • Author(s): Kunimi K, Usui Y, Tsubota K, Mitsuhashi R, Umazume A, Kezuka T, Sakai J, Goto H.
  • Journal Title: Ocul Immunol Inflamm Volume: - Issue: 5 Pages: 976-981
  • DOI: 10.1080/09273948.2019.1709649
  • Peer Reviewed / Open Access
• [Journal Article] Share Successful Treatment of Necrotizing Retinitis with Epstein-Barr Virus-Positive Ocular Fluid by Intravitreal Methotrexate Injection. (2020)
  • Author(s): Mashima A, Usui Y, Umazume K, Muramatsu D, Goto H.
  • Journal Title: Ocul Immunol Inflamm Volume: 28 Issue: 4 Pages: 552-555
  • DOI: 10.1080/09273948.2019.1609047
  • Peer Reviewed / Open Access
• [Journal Article] Primary Intraocular Methotrexate-related Lymphoproliferative Disorder in a Patient with Rheumatoid Arthritis Undergoing Long-term Methotrexate Therapy. (2020)
  • Author(s): Sone K, Usui Y, Fujii K, Goto H.
  • Journal Title: Ocul Immunol Inflamm Volume: - Issue: 3 Pages: 456-459
  • DOI: 10.1080/09273948.2019.1668428
  • Peer Reviewed
• [Journal Article] Evaluation of retinal pigment epithelium layer change in Vogt-Koyanagi- Harada disease with multicontrast optical coherence tomography (2019)
  • Author(s): Miura M, Makita S, Azuma S,Yasuno Y, Sugiyama S, Mino M, Yamaguchi T, Agawa T, Iwasaki T, Usui Y, Rao NA, Goto H
  • Journal Title: Invest Ophthalmol Vis Sci Volume: 60 Issue: 10 Pages: 3352-3362
  • DOI: 10.1167/iovs.19-27378
  • NAID: 120007132697
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 炎症性眼疾患における新規バイオマーカーの創出-古典的検査からオミックス解析まで- (2020)
  • Author(s): 臼井嘉彦
  • Organizer: 第124回日本眼科学会総会
  • Invited
• [Presentation] 非感染性ぶどう膜炎の患者血清を用いた網羅的miRNAの解析 (2020)
  • Author(s): 朝蔭正樹、臼井嘉彦、禰津直也、清水広之、坪田欣也、山川直之、梅津知宏、高梨正勝、黒田雅彦、後藤浩
  • Organizer: 第124回日本眼科学会総会
• [Presentation] メタボロミクスによる血清を用いた３大ぶどう膜炎の鑑別 (2020)
  • Author(s): 清水広之、臼井嘉彦、禰津直也、朝蔭正樹、杉本昌弘、後藤浩
  • Organizer: 第124回日本眼科学会総会
• [Presentation] メタボロミクスを用いた眼サルコイドーシスにおける水溶性代謝物の網羅的解析 (2020)
  • Author(s): 菅原莉沙、清水広之、臼井嘉彦、坪田欣也、禰津直也、朝蔭正樹、杉本昌弘、後藤浩
  • Organizer: 第124回日本眼科学会総会
• [Presentation] 眼内リンパ腫における硝子体液を用いたプロテオミクス解析 (2020)
  • Author(s): 坪田欣也、臼井嘉彦、禰津直也、朝蔭正樹、清水広之、山川直之、植田幸嗣、山口剛司、後藤浩
  • Organizer: 第124回日本眼科学会総会
• [Presentation] 眼窩リンパ増殖性疾患におけるmiRNAの網羅的解析 (2020)
  • Author(s): 禰津直也、臼井嘉彦、朝蔭正樹、清水広之、坪田欣也、山川直之、高梨正勝、黒田雅彦、後藤浩
  • Organizer: 第124回日本眼科学会総会
• [Presentation] 眼内リンパ腫とサルコイドーシス患者の硝子体および血清中の網羅的miRNA解析 (2020)
  • Author(s): 嶺崎輝海、臼井嘉彦、朝蔭正樹、禰津直也、清水広之、山川直之、成松明知、坪田欣也、馬詰和比古、黒田雅彦、後藤浩
  • Organizer: 第124回日本眼科学会総会
• [Presentation] サルコイドーシスによるぶどう膜炎に対するアダリムマブ導入例の検討 (2020)
  • Author(s): 國見敬子、臼井嘉彦、坪田欣也、馬詰朗比古、毛塚剛司、坂井潤一、後藤浩
  • Organizer: 第124回日本眼科学会総会
• [Presentation] 眼内リンパ腫における採血結果および硝子体液中サイトカイン濃度を用いたクラスター解析 (2019)
  • Author(s): 坪田欣也、臼井嘉彦、後藤浩
  • Organizer: 第37回日本眼腫瘍学会
• [Presentation] 機械学習を用いた硝子体液中の免疫液性因子解析による眼内リンパ腫の識別検討 (2019)
  • Author(s): 禰津直也、臼井嘉彦、坪田欣也、朝蔭正樹、山川直之、黒田雅彦、斎藤彰、杉本昌弘、後藤浩
  • Organizer: 第37回日本眼腫瘍学会
• [Presentation] 眼内リンパ腫患者硝子体液および血清中における網羅的miRNA解析 (2019)
  • Author(s): 臼井嘉彦、朝蔭正樹、禰津直也、清水広之、成松明知、坪田欣也、馬詰和比古、後藤浩、黒田雅彦
  • Organizer: 第37回日本眼腫瘍学会
• [Presentation] 機械学習を用いた前房水中の免疫液性因子解析による眼内炎症性疾患の識別検討 (2019)
  • Author(s): 禰津直也、臼井嘉彦、朝蔭正樹、清水広之、斎藤彰、黒田雅彦、後藤浩
  • Organizer: 第７３回日本臨床眼科学会
• [Presentation] 眼サルコイドーシスにおける採血データを用いた階層型クラスター解析 (2019)
  • Author(s): 松島亮介、臼井嘉彦、清水広之、坪田欣也、後藤浩
  • Organizer: 第７３回日本臨床眼科学会