Novel experimental model of TTR amyloidosis using TTR fragments

• Project/Area Number: 15K09318
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Kumamoto University
• Principal Investigator: Ueda Mitsuharu 熊本大学, 医学部附属病院, 講師 (60452885)
• Co-Investigator(Kenkyū-buntansha): 水口 峰之 富山大学, 大学院医学薬学研究部(薬学), 教授 (30332662) ; 山中 邦俊 熊本大学, 発生医学研究所, 准教授 (90212290)
• Co-Investigator(Renkei-kenkyūsha): MISUMI Yohei 熊本大学, 医学部附属病院, 助教 (80625781) ; YAMASHITA Taro 熊本大学, 医学部附属病院, 特任教授 (90381003) ; OGURA Teru 熊本大学, 発生医学研究所, 教授 (00158825) ; ANDO Yukio 熊本大学, 生命科学研究部, 教授 (20253742)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 家族性アミロイドポリニューロパチー / トランスサイレチン / アミロイドーシス / 抗体治療 / ドラッグリポジショニング / 病態モデル / アミロイド

Outline of Final Research Achievements

We developed a novel experimental model of TTR amyloidosis using TTR fragments, which easily form amyloid fibrils in vitro. Those TTR fragments induced apoptosis in cultured cells. We also performed drug screening using this experimental model and found several candidates of TTR amyloid inhibitors.

Research Products

• [Int'l Joint Research] Indiana University(米国)
• [Journal Article] Diagnostic utility of cardiac troponin T level in patients with cardiac amyloidosis. (2018)
  • Author(s): Takashio S, Yamamuro M, Izumiya Y, Hirakawa K, Marume K, Yamamoto M, Ueda M, Yamashita T, Ishibashi-Ueda H, Yasuda S, Ogawa H, Ando Y, Anzai T, Tsujita K
  • Journal Title: ESC Heart Fail Volume: 5 Issue: 1 Pages: 27-35
  • DOI: 10.1002/ehf2.12203
  • Peer Reviewed / Open Access
• [Journal Article] Genetic and clinical characteristics of hereditary transthyretin amyloidosis in endemic and non-endemic areas: experience from a single-referral center in Japan. (2018)
  • Author(s): Yamashita T, Ueda M, Misumi Y, Masuda T, Nomura T, Tasaki M, Takamatsu K, Sasada K, Obayashi K, Matsui H, Ando Y.
  • Journal Title: Journal of Neurology Volume: 265 Issue: 1 Pages: 134-140
  • DOI: 10.1007/s00415-017-8640-7
  • Peer Reviewed / Open Access
• [Journal Article] Nationwide Survey of 741 Patients with Systemic Amyloid Light-chain Amyloidosis in Japan (2018)
  • Author(s): Shimazaki C, Hata H, Iida S, Ueda M, Katoh N, Sekijima Y, Ikeda S, Yazaki M, Fukushima W, Ando Y
  • Journal Title: Internal Medicine Volume: 57 Issue: 2 Pages: 181-187
  • DOI: 10.2169/internalmedicine.9206-17
  • NAID: 130006309174
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed / Open Access
• [Journal Article] Loss of CYLD promotes cell invasion via ALK5 stabilization in oral squamous cell carcinoma (2018)
  • Author(s): Shinriki S, Jono H, Maeshiro M, Nakamura T, Guo J, Li JD, Ueda M, Yoshida R, Shinohara M, Nakayama H, Matsui H, Ando Y.
  • Journal Title: Journal of Pathology Volume: 244 Issue: 3 Pages: 367-379
  • DOI: 10.1002/path.5019
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Unwanted road to anemia in transthyretin familial amyloid polyneuropathy may continue irrespective of tafamidis treatment (2018)
  • Author(s): Ikeda T, Masuda T, Ueda M, Yamashita T, Misumi Y, Shinriki S, Ando Y.
  • Journal Title: Annals of Clinical Biochemistry Volume: 印刷中 Issue: 5 Pages: 571-575
  • DOI: 10.1177/0004563218754587
  • Peer Reviewed / Open Access
• [Journal Article] Patisiran, a RNAi therapeutic, for hereditary transthyretin amyloidosis. (2018)
  • Author(s): Adams D, Gonzalez-Duarte A, O’Riordan W, Yang C, Ueda M, et al.
  • Journal Title: N Engl J Med Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Clinicopathological and biochemical findings of thyroid amyloid in hereditary transthyretin amyloidosis with and without liver transplantation. (2017)
  • Author(s): Huang G, Ueda M, Tasaki M, Yamashita T, Misumi Y, Masuda T, Suenaga G, Inoue Y, Kinoshita Y, Matsumoto S, Mizukami M, Tsuda Y, Nomura T, Obayashi K, Ando Y
  • Journal Title: Amyloid Volume: 印刷中 Issue: 1 Pages: 1-6
  • DOI: 10.1080/13506129.2016.1276440
  • Peer Reviewed
• [Journal Article] Identification and Assessment of Cardiac Amyloidosis by Myocardial Strain Analysis of Cardiac Magnetic Resonance Imaging (2017)
  • Author(s): Oda S, Utsunomiya D, Nakaura T, Yuki H, Kidoh M, Morita K, Takashio S, Yamamuro M, Izumiya Y, Hirakawa K, Ishida T, Tsujita K, Ueda M, Yamashita T, Ando Y, Hata H, Yamashita Y
  • Journal Title: Circulation Journal Volume: 81 Issue: 7 Pages: 1014-1021
  • DOI: 10.1253/circj.CJ-16-1259
  • NAID: 130006887042
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Open Access
• [Journal Article] Novel screening for transthyretin amyloidosis by using fat ultrasonography. (2017)
  • Author(s): Misumi Y, Ueda M, Yamashita T, Masuda T, Kinoshita Y, Tasaki M, Nagase T, Ando Y
  • Journal Title: Ann Neurol Volume: 印刷中 Issue: 4 Pages: 604-608
  • DOI: 10.1002/ana.24914
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Early skin denervation in hereditary and iatrogenic transthyretin amyloid neuropathy. (2017)
  • Author(s): Masuda T, Ueda M, Suenaga G, Misumi Y, Tasaki M, Izaki A, Yanagisawa Y, Inoue Y, Motokawa H, Matsumoto S, Mizukami M, Arimura A, Deguchi T, Nishio Y, Yamashita T, Inomata Y, Obayashi K, Ando Y
  • Journal Title: Neurology Volume: 88 Issue: 23 Pages: 2192-2197
  • DOI: 10.1212/wnl.0000000000004016
  • Peer Reviewed / Open Access
• [Journal Article] Cardiovascular magnetic resonance myocardial T1 mapping to detect and quantify cardiac involvement in familial amyloid polyneuropathy. (2017)
  • Author(s): Oda S, Utsunomiya D, Morita K, Nakaura T, Yuki H, Kidoh M, Hirata K, Taguchi N, Tsuda N, Shiraishi S, Namimoto T, Hirakawa K, Takashio S, Izumiya Y, Yamamuro M, Hokimoto S, Tsujita K, Ueda M, Yamashita T, Ando Y, Yamashita Y
  • Journal Title: Eur Radiol Volume: 27(11) Issue: 11 Pages: 4631-4638
  • DOI: 10.1007/s00330-017-4845-5
  • Peer Reviewed / Open Access
• [Journal Article] Inflammatory state exists in familial amyloid polyneuropathy that may be triggered by mutated transthyretin. (2017)
  • Author(s): Suenaga G, Ikeda T, Masuda T, Motokawa H, Yamashita T, Takamatsu K, Misumi Y, Ueda M, Matsui H, Senju S, Ando Y.
  • Journal Title: Sci. Rep Volume: 7(1) Issue: 1 Pages: 1579-2017
  • DOI: 10.1038/s41598-017-01775-4
  • Peer Reviewed / Open Access
• [Journal Article] Sushi repeat-containing protein 1: a novel disease-associated molecule in cerebral amyloid angiopathy. (2017)
  • Author(s): Inoue Y, Ueda M, Tasaki M, Takeshima A, Nagatoshi A, Masuda T, Misumi Y, Kosaka T, Nomura T, Mizukami M, Matsumoto S, Yamashita T, Takahashi H, Kakita A, Ando Y.
  • Journal Title: Acta Neuropathologica Volume: 134 Issue: 4 Pages: 605-617
  • DOI: 10.1007/s00401-017-1720-z
  • Peer Reviewed / Open Access
• [Journal Article] Serum amyloid P component: A novel potential player in vessel degeneration in CADASIL. (2017)
  • Author(s): Nagatoshi A, Ueda M, Ueda A, Tasaki M, Inoue Y, Ma Y, Masuda T, Mizukami M, Matsumoto S, Kosaka T, Kawano T, Ito T, Ando Y.
  • Journal Title: Journal of the Neurological Sciences Volume: 379 Pages: 69-76
  • DOI: 10.1016/j.jns.2017.05.033
  • Peer Reviewed
• [Journal Article] A multicenter cross sectional study for bone-articular lesions associated with dialysis related amyloidosis in Japan. (2017)
  • Author(s): Nishi S, Hoshino J, Yamamoto S, Goto S, Fuji H, Ubara Y, Motomiya Y, Morita H, Takaichi K, Yamagata K, Shigematsu T, Ueda M, Ando Y
  • Journal Title: Nephrology Volume: 印刷中 Issue: 7 Pages: 640-645
  • DOI: 10.1111/nep.13077
  • Peer Reviewed / Open Access
• [Journal Article] A novel transthyretin variant V28S (p.V48S) with a double-nucleotide substitution in the same codon. (2017)
  • Author(s): Okada M, Misumi Y, Ueda M, Yamashita T, Masuda T, Tasaki M, Ando Y.
  • Journal Title: Amyloid Volume: 24 Issue: 4 Pages: 231-232
  • DOI: 10.1080/13506129.2017.1381082
  • Peer Reviewed
• [Journal Article] First nationwide survey on systemic wild-type ATTR amyloidosis in Japan (2017)
  • Author(s): Sekijima Y、Yazaki M、Ueda M、Koike H、Yamada M、Ando Y
  • Journal Title: Amyloid Volume: 25 Issue: 1 Pages: 8-10
  • DOI: 10.1080/13506129.2017.1409706
  • Peer Reviewed
• [Journal Article] Effects of tafamidis treatment on transthyretin (TTR) stabilization, efficacy, and safety in Japanese patients with familial amyloid polyneuropathy (TTR-FAP) with Val30Met and non-Varl30Met: A phase III, open-label study. (2016)
  • Author(s): Ando Y, Sekijima Y, Obayashi K, Yamashita T, Ueda M, Misumi Y, Morita H, Machii K, Ohta M, Takata A, Ikeda S.
  • Journal Title: J Neurol Sci Volume: 362 Pages: 266-271
  • DOI: 10.1016/j.jns.2016.01.046
  • Peer Reviewed / Open Access
• [Journal Article] Involvement of macrophages in the pathogenesis of familial amyloid polyneuropathy and efficacy of human iPS cell-derived macrophages in its treatment. (2016)
  • Author(s): Suenaga G, Ikeda T, Komohara Y, Takamatsu K, Kakuma T, Tasaki M, Misumi Y, Ueda M, Ito T, Senju S, Ando Y
  • Journal Title: PLoS One Volume: 11 Issue: 10 Pages: e0163944-e0163944
  • DOI: 10.1371/journal.pone.0163944
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Novel antibody for the treatment of transthyretin amyloidosis. (2016)
  • Author(s): Hosoi A, Su Y, Torikai M, Jono H, Ishikawa D, Soejima K, Higuchi H, Guo J, Ueda M, Suenaga G, Motokawa H, Ikeda T, Senju S, Nakashima T, Ando Y
  • Journal Title: J Biol Chem Volume: 25 Issue: 48 Pages: 25096-25105
  • DOI: 10.1074/jbc.m116.738138
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Diagnostic significance of cortical superficial siderosis for Alzheimer’s disease in patients with cognitive impairment. (2016)
  • Author(s): Inoue Y, Nakajima M, Uetani H, Hirai T, Ueda M, Kitajima M, Utsunomiya D, Watanabe M, Hashimoto M, Ikeda M, Yamashita Y, Ando Y.
  • Journal Title: AJNR Am J Neuroradiol Volume: 37 Issue: 2 Pages: 223-227
  • DOI: 10.3174/ajnr.a4496
  • Peer Reviewed / Open Access
• [Journal Article] Knee osteoarthritis associated with different kinds of amyloid deposits and the impact of aging on type of amyloid. (2016)
  • Author(s): Yanagisawa A, Ueda M, Sueyoshi T, Nakamura E, Tasaki M, Suenaga G, Motokawa H, Toyoshima R, Kinoshita Y, Misumi Y, Yamashita T, Sakaguchi M, Westermark P, Mizuta H, Ando Y.
  • Journal Title: Amyloid Volume: 23 Issue: 1 Pages: 26-32
  • DOI: 10.3109/13506129.2015.1115758
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Labial salivary gland biopsy for diagnosing immunoglobulin light chain amyloidosis: a retrospective analysis. (2016)
  • Author(s): Suzuki T, Kusumoto S, Yamashita T, Masuda A, Kinoshita S, Yoshida T, Takami-Mori F, Takino H, Ito A, Ri M, Ishida T, Komatsu H, Ueda M, Ando Y, Inagaki H, Iida S.
  • Journal Title: Annals of Hematology Volume: 95 (2) Issue: 2 Pages: 279-285
  • DOI: 10.1007/s00277-015-2549-y
  • Peer Reviewed / Open Access
• [Journal Article] Long-term outcome of patients with hereditary transthyretin V30M amyloidosis with polyneuropathy after liver transplantation. (2016)
  • Author(s): Okumura K, Yamashita T, Masuda T, Misumi Y, Ueda A, Ueda M, Obayashi K, Jono H, Yamashita S, Inomata Y, Ando Y.
  • Journal Title: Amyloid Volume: 23 Issue: 1 Pages: 39-45
  • DOI: 10.3109/13506129.2015.1123149
  • Peer Reviewed
• [Journal Article] Endoscopic findings of the small-bowel lesions in familial amyloid polyneuropathy: a case report. (2016)
  • Author(s): Asakura, K, Yanai S, Nakamura S, Kawasaki, K, Eizuka M, Ishida K, Sugai T, Ueda M, Yamashita T, Ando Y, Matsumoto T.
  • Journal Title: Medicine Volume: 95
  • Peer Reviewed
• [Journal Article] Sources of variation of transthyretin in healthy subjects in East and Southeast Asia: Clinical and experimental evidence for the effect of alcohol on transthyretin metabolism. (2016)
  • Author(s): Jono H, Su Y, Obayashi K, Tanaka Y, Ishiguro A, Nishimura H, Shinriki S, Ueda M, Ikeda K, Yamagata K, Ichihara K, Ando Y; Scientific Committee for the Asia-Pacific Federation of Clinical Biochemistry.
  • Journal Title: Clin Chim Acta Volume: 458 Pages: 240-5
  • DOI: 10.1016/j.cca.2016.04.011
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Recipient Aging Accelerates Acquired Transthyretin Amyloidosis After Domino Liver Transplantation. (2015)
  • Author(s): Misumi Y., Narita Y., Oshima T., Ueda M., Yamashita T., Tasaki M., Obayashi K., Isono K., Inomata Y., Ando Y.
  • Journal Title: Liver Transpl Volume: 22(5) Issue: 5 Pages: 656-664
  • DOI: 10.1002/lt.24371
  • Peer Reviewed / Open Access
• [Journal Article] Inhibition of insulin amyloid fibril formation by cyclodextrins. (2015)
  • Author(s): Kitagawa K, Misumi Y, Ueda M, Hayashi Y, Tasaki M, Obayashi K, Yamashita T, Jono H, Arima H, Ando Y.
  • Journal Title: Amyloid Volume: 22 Issue: 3 Pages: 181-186
  • DOI: 10.3109/13506129.2015.1064818
  • Peer Reviewed
• [Journal Article] Discovery of γ-Mangostin as an Amyloidogenesis Inhibitor. (2015)
  • Author(s): Yokoyama T, Ueda M, Ando Y, Mizuguchi M.
  • Journal Title: Sci Rep Volume: 5 Issue: 1 Pages: 13570-13570
  • DOI: 10.1038/srep13570
  • Peer Reviewed / Open Access
• [Journal Article] Two brothers homozygous for the TTR V30M both presenting with a phenotype dominated by central nervous complications. (2015)
  • Author(s): Uchida Y, Takada K, Tsugu Y, Ueda M, Yamashita T, Ando Y, Kobayashi S, Koike H, Watanabe T, Matsumoto T, Toyoda T, Yamada G, Matsukawa N.
  • Journal Title: Amyloid Volume: 22 Issue: 4 Pages: 261-262
  • DOI: 10.3109/13506129.2015.1104661
  • Peer Reviewed
• [Journal Article] Rapid detection of wild-type and mutated transthyretins. (2015)
  • Author(s): Tasaki M, Ueda M, Obayashi K, Motokawa H, Kinoshita Y, Suenaga G, Yanagisawa A, Toyoshima R, Misumi Y, Masuda T, Yamashita T, Ando Y.
  • Journal Title: Ann Clin Biochem
  • Peer Reviewed
• [Presentation] Early diagnosis and therapies for hereditary transthyretin amyloidosis. (2018)
  • Author(s): Ueda M
  • Organizer: XVI International Symposium on Amyloidosis.
  • Int'l Joint Research / Invited
• [Presentation] Redefining the patient and treatment paradigm. (2018)
  • Author(s): Ueda M, Masuda T, Misumi Y, Yamashita T, Ando Y.
  • Organizer: XVI International Symposium on Amyloidosis.
  • Int'l Joint Research / Invited
• [Presentation] Early skin denervation in transthyretin amyloid neuropathy. Driving change: Novel research into early screening and diagnosis of hereditary transthyretin amyloidosis polyneuropathy. (2017)
  • Author(s): Ueda M, Masuda T, Ando Y.
  • Organizer: PNS 2017 annual meeting.
  • Int'l Joint Research / Invited
• [Presentation] Amyloid formation and toxicity of fragmented transthyretin. (2017)
  • Author(s): Ueda M, Misumi Y, Masuda T, Tsuda Y, Inoue Y, Tasaki M, Yamashita T, Ando Y.
  • Organizer: XXIII World Congress of Neurology.
  • Int'l Joint Research
• [Presentation] Novel findings of amyloidosis: Analyses by mass spectrometry. Clinical Mass Spectrometry Meeting Anatomical and Chemical Pathology. (2017)
  • Author(s): Ueda M, Tasaki M, Inoue Y, Ando Y.
  • Organizer: The 29th World Congress of World Association of Societies of Pathology and Laboratory Medicine.
  • Int'l Joint Research / Invited
• [Presentation] Novel diagnostic and treatment strategies in amyloidosis. (2017)
  • Author(s): Ueda M, Masuda T, Misumi Y, Tasaki M, Inoue Y, Yamashita T, Ando Y.
  • Organizer: Medical and Nursing Symposium between Shandong University and Kumamoto University.
  • Int'l Joint Research / Invited
• [Presentation] アミロイドアンギオパチーの病態と治療の展望． (2016)
  • Author(s): 植田光晴、井上泰輝、山下太郎、安東由喜雄
  • Organizer: 第59回日本腎臓学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2016-07-17
  • Invited
• [Presentation] Role of C-terminal portion of transthyretin on amyloid formation. (2016)
  • Author(s): Ueda M, Mizuguchi M, Misumi Y, Tasaki M, Suenaga G, Matsumoto S, Mizukami M, Masuda T, Yamashita T, Kluve-Beckerman B, Liepnieks JJ, Benson MD, Ando Y.
  • Organizer: The XVth International Symposium on Amyloidosis.
  • Place of Presentation: Uppsala, Sweden
  • Year and Date: 2016-07-03
  • Int'l Joint Research
• [Presentation] Amyloid formation of C-terminal portion of transthyretin. (2016)
  • Author(s): Ueda M, Mizuguchi M, Misumi Y, Masuda T, Tasaki M, Suenaga G, Inoue Y, Tsuda Y, Nomura T, Kinoshita Y, Matsumoto S, Mizukami M, Yamashita T, Ando Y.
  • Organizer: 第57回日本神経学会学術大会
  • Place of Presentation: 神戸
  • Year and Date: 2016-05-18
• [Presentation] TTRアミロイドーシスの治療法開発． (2016)
  • Author(s): 植田光晴、安東由喜雄
  • Organizer: 第４回日本アミロイドーシス研究会学術集会
  • Place of Presentation: 東京
  • Invited
• [Presentation] 家族性アミロイドポリニューロパチーの病態解析と新たな治療戦略への展開． (2015)
  • Author(s): 植田光晴、安東由喜雄
  • Organizer: 第38回日本分子生物学会年会, 第88回日本生化学会大会 合同大会
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-01
  • Invited
• [Presentation] トランスサイレチンアミロイドーシスの病態解析と新たな治療戦略． (2015)
  • Author(s): 植田光晴、安東由喜雄
  • Organizer: 第3回日本アミロイドーシス研究会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2015-08-21
  • Invited
• [Presentation] 家族性アミロイドポリニューロパチーの病態解析と治療における展望． (2015)
  • Author(s): 植田光晴、安東由喜雄
  • Organizer: 第56回日本神経学会学術大会
  • Place of Presentation: 新潟
  • Year and Date: 2015-05-20
  • Invited
• [Remarks] 熊本大学 神経内科のホームぺジ
  • URL: http://www2.kuh.kumamoto-u.ac.jp/neurology/