Acceleration of the definition of "inflammasome disease" based on molecular mechanism of diseases

• Project/Area Number: 17K19685
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Research Field: Internal medicine of the bio-information integration and related fields
• Research Institution: Ehime University
• Principal Investigator: MASUMOTO Junya 愛媛大学, プロテオサイエンスセンター, 教授 (20334914)
• Co-Investigator(Kenkyū-buntansha): 座古 保 愛媛大学, 理工学研究科(理学系), 教授 (50399440) ; 大澤 春彦 愛媛大学, 医学系研究科, 教授 (90294800)
• Research Collaborator: Kaneko naoe 愛媛大学, 医学系研究科
• Project Period (FY): 2017-06-30 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2018: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000); Fiscal Year 2017: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
• Keywords: インフラマソーム病 / コンパニオン診断 / 難病

Outline of Final Research Achievements

The purpose of this study is that the definition of new diagnostic categories based on molecular mechanism of the diseases. We constructed inflammasomes in a cell-free system using a wheat germ cell-free protein synthesis system. We also prepared amyloid β which characterized by Alzheimer's disease and amylin which characterized by type 2 diabetes. We demonstrated that amyloid β oligomers deposited in the brain in Alzheimer's disease directly induce the binding of NLRP3 to ASC, which is the first step in NLRP3 inflammasome formation. In order to prove that all these diseases are inflammasome diseases, we constructed antibodises against cell-free inflammasome complexes.

Academic Significance and Societal Importance of the Research Achievements

本研究の目的は、臨床症状や病理形態に基づいた現在の難病診断を、正確な分子機序に基づいた分子標的治療に直結した新規の診断カテゴリーの創設へと再編成することである。これまで難治性炎症疾患などは、症状を点数化した臨床診断や、形態学的な病理診断に基づいて行われており、診断と治療効果が直結しないことや、確定診断に至らず治療に難渋することも少なくない。そこで、正確な分子機序に基づいた診断と疾患の再編成が必要である。上述の研究成果で『インフラマソーム病』を定義することにより、分子標的に基づいた疾患の再編成が進むものと考えられる。

Research Products

• [Journal Article] The role of interleukin-1 in general pathology (2019)
  • Author(s): Kaneko N, Kurata M, Yamamoto T, Morikawa S, Masumoto J.
  • Journal Title: Inflammation and Regeneration Volume: 印刷中 Issue: 1 Pages: 12-12
  • DOI: 10.1186/s41232-019-0101-5
  • Peer Reviewed / Open Access
• [Journal Article] Clinical features and new diagnostic criteria of the syndrome of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) (2019)
  • Author(s): Takeuchi Y, Shigemura T, Kobayashi N, Nagumo H, Furumoto M, Ogasawara K, Fujii H, Takizawa M, Soga T, Matoba H, Masumoto J, Fukushima K, Migita K, Ojima T, Umeda Y, AgematsuK.
  • Journal Title: International Journal of Rheumatic Diseases Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Amyloid β directly interacts with NLRP3 to initiate inflammasome activation: identification of an intrinsic NLRP3 ligand in a cell-free system (2018)
  • Author(s): Nakanishi Ayaka、Kaneko Naoe、Takeda Hiroyuki、Sawasaki Tatsuya、Morikawa Shinnosuke、Zhou Wei、Kurata Mie、Yamamoto Toshihiro、Akbar Sheikh Mohammad Fazle、Zako Tamotsu、Masumoto Junya
  • Journal Title: Inflammation and Regeneration Volume: 38 Issue: 1 Pages: 27-27
  • DOI: 10.1186/s41232-018-0085-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Musculoskeletal manifestations occur predominantly in patients with later-onset familial Mediterranean fever: Data from a multicenter, prospective national cohort study in Japan. (2018)
  • Author(s): Endo Y, Koga T, Ishida M, Fujita Y, Tsuji S, Takatani A, Shimizu T, Sumiyoshi R, Igawa T, Umeda M, Fukui S, Nishino A, Kawashiri SY, Iwamoto N, Ichinose K, Tamai M, Nakamura H, Origuchi T, Agematsu K, Yachie A, Masumoto J, Migita K, Kawakami A.
  • Journal Title: Arthritis Res Ther. Volume: 20 Issue: 1 Pages: 257-257
  • DOI: 10.1186/s13075-018-1738-1
  • NAID: 120006987889
  • Peer Reviewed / Open Access
• [Journal Article] IAPP/amylin deposition, which is correlated with expressions of ASC and IL-1β in β-cells of Langerhans’ islets, directly initiates NLRP3 inflammasome activation (2018)
  • Author(s): Morikawa S, Kaneko N, Okumura C, Taguchi H, Kurata M, Yamamoto T, Osawa H, Nakanishi A, Zako T, Masumoto J.
  • Journal Title: International Journal of Immunopathology and Pharmacology Volume: 32 Pages: 205873841878874-205873841878874
  • DOI: 10.1177/2058738418788749
  • Peer Reviewed / Open Access
• [Journal Article] Analysis of biomarker serum levels in IVIG and infliximab refractory Kawasaki disease patients (2018)
  • Author(s): Hachiya A, Kobayashi N, Matsuzaki S, Takeuchi Y, Akazawa Y, Shigemura T, Motoki N, Masumoto J, Agematsu K.
  • Journal Title: Clinical Rheumatology Volume: 37 Issue: 7 Pages: 1937-1943
  • DOI: 10.1007/s10067-017-3952-7
  • Peer Reviewed
• [Journal Article] MicroRNA-204-3p inhibits lipopolysaccharide-induced cytokines in familial Mediterranean fever via the phosphoinositide 3-kinase γ pathway (2017)
  • Author(s): Koga Tomohiro,Migita Kiyoshi,Sato Tomohito,Sato Shuntaro,Umeda Masataka,Nonaka Fumiaki,Fukui Shoichi,Kawashiri Shin-ya,Iwamoto Naoki,Ichinose Kunihiro,Tamai Mami,Nakamura Hideki,Origuchi Tomoki,Ueki Yukitaka,Masumoto Junya,Agematsu Kazunaga,Yachie Akihiro,Yoshiura Koh-ichiro,Eguchi Katsumi,Kawakami Atsushi
  • Journal Title: Rheumatology Volume: 57 Issue: 4 Pages: 718-726
  • DOI: 10.1093/rheumatology/kex451
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Comparison of serum inflammatory cytokine concentrations in familial Mediterranean fever and rheumatoid arthritis patients (2017)
  • Author(s): Koga T、Kawashiri S-y、Migita K、Sato S、Umeda M、Fukui S、Nishino A、Nonaka F、Iwamoto N、Ichinose K、Tamai M、Nakamura H、Origuchi T、Ueki Y、Masumoto J、Agematsu K、Yachie A、Eguchi K、Kawakami A
  • Journal Title: Scandinavian Journal of Rheumatology Volume: - Issue: 4 Pages: 1-3
  • DOI: 10.1080/03009742.2017.1363281
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Early diagnosis of early-onset sarcoidosis: a case report with functional analysis and review of the literature. (2017)
  • Author(s): Takeuchi Y, Shigemura T, Kobayashi N, Kaneko N, Iwasaki T, Minami K, Kobayashi K, Matsumoto J, Agematsu K.
  • Journal Title: Clinical Rheumatology Volume: 36 Issue: 5 Pages: 1189-1196
  • DOI: 10.1007/s10067-017-3544-6
  • Peer Reviewed / Open Access
• [Journal Article] Applications of reconstituted inflammasomes in a cell-free system to drug discovery and elucidation of the pathogenesis of autoinflammatory diseases. (2017)
  • Author(s): Kaneko N, Iwasaki T, Ito Y, Takeda H, Sawasaki T, Morikawa S, Nakano N, Kurata M, Masumoto J.
  • Journal Title: Inflammation and Regeneration Volume: 印刷中 Issue: 1 Pages: 9-9
  • DOI: 10.1186/s41232-017-0040-y
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Poly (I:C) and hyaluronic acid directly interact with NLRP3, resulting in the assembly of NLRP3 and ASC in a cell-free system. (2017)
  • Author(s): Kaneko N, Ito Y, Iwasaki T, Takeda H, Sawasaki T, Migita K, Agematsu K, Koga T, Kawakami A, Yachie A, Yoshiura K, Morikawa S, Kurata M, Masumoto J.
  • Journal Title: European Journal of Inflammation Volume: 印刷中 Issue: 2 Pages: 85-97
  • DOI: 10.1177/1721727x17711047
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Quantitative evaluation of mRNA expression of MEFV gene product pyrin in human tissues (2018)
  • Author(s): Nakano N, Kaneko N, Kurata N, Yamamoto T, Urano T, Koga T, Kawakami A, Yachie A, Agematsu K, Migita K, Yoshiura K, Ishii E, Masumoto J
  • Organizer: European Society for Immunodeficiencies 2018
  • Int'l Joint Research
• [Presentation] インフラマソーム活性化メカニズム解説のための擬人化(キャラクター化)を用いた漫画(マンガ) によるアウトリーチ活動の試み (2018)
  • Author(s): 和田有希子, 金子直恵, 増本純也.
  • Organizer: 第41回分子生物学会年会
• [Presentation] Aβのアミロイド凝集体によるNLRP3インフラマソームの活性化 (2018)
  • Author(s): 中西文香、金子直恵、座古保、増本純也.
  • Organizer: 第41回分子生物学会年会
• [Presentation] アミロイドAβの重合化は試験管内無細胞インフラマソームの形成を促進する (2018)
  • Author(s): 金子直恵、中西文香、座古保、増本純也.
  • Organizer: 第39回日本炎症・再生医学会
• [Presentation] 無細胞タンパク質複合体再構成系による自己炎症疾患の病態解明と特異的分子標的治療薬探索 (2018)
  • Author(s): 増本純也, 金子直恵, 伊藤有紀, 山本敏弘, 倉田美恵, 中野直子, 森川紳之祐, 周薇, 竹田浩之, 澤崎達也
  • Organizer: 第1回日本免疫不全・自己炎症学会総会・学術集会
  • Invited
• [Presentation] 無細胞系によるNLRP3と直接相互作用する内因性物質の同定 (2017)
  • Author(s): 増本純也, 金子直恵, 伊藤有紀
  • Organizer: 第38回日本炎症・再生医学会
• [Presentation] 無細胞系によるNLRP3インフラソームと直接相互作用する物質の探索 (2017)
  • Author(s): 増本純也, 金子直恵, 伊藤有紀, 森川紳之祐, 山本敏弘, 倉田美恵
  • Organizer: 第12回臨床ストレス応答学会大会
• [Remarks] 愛媛大学プロテオサイエンスセンター 病理学部門
  • URL: http://www.pros.ehime-u.ac.jp/section/09.html