Analysis and development of medical treatment for autoinflammatory diseases

• Project/Area Number: 23249056
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Kyoto University
• Principal Investigator: HEIKE TOSHIO 京都大学, 医学(系)研究科(研究院), 教授 (90190173)
• Co-Investigator(Kenkyū-buntansha): NISHIKOMORI Ryuta 京都大学, 医学研究科, 准教授 (70359800) ; YASUMI Takahiro 京都大学, 医学研究科, 講師 (00511891) ; OHARA Osamu (財)かずさDNA研究所, ヒトゲノム研究部, 部長 (20370926) ; KAMBE Naotomo 千葉大学, 医学研究科, 講師 (50335254)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥47,840,000 (Direct Cost: ¥36,800,000、Indirect Cost: ¥11,040,000); Fiscal Year 2013: ¥14,820,000 (Direct Cost: ¥11,400,000、Indirect Cost: ¥3,420,000); Fiscal Year 2012: ¥15,730,000 (Direct Cost: ¥12,100,000、Indirect Cost: ¥3,630,000); Fiscal Year 2011: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000)
• Keywords: 自己炎症性疾患 / インフラマソーム / モザイシズム / CAPS / 高IgD症候群 / NLRP3 / インフラマゾーム / 次世代シークエンサー / 軟骨細胞 / 自然免疫 / 自己炎症疾患 / mevalonate kinase

Research Abstract

Autoinflammatory disease is a new entity of inflammatory disorder, characterized by periodic fever. Although it is comprehended that autoinflammatory disease is caused by inflammatory cytokine production through dysregulated inflammasome function, many aspects are still remained to be resolved from the view point of molecular mechanism. Moreover, it is not well evaluated that multiple organ pathophysiology is all derived from dysregulated inflammasome function. Base on this fund, we develop the evaluation of autoinflammatory disease through patient-derived samples, disease-specific iPS cells, animal model experiment, and new medical technology such as next generation sequencing. These results lead to the establishment of medical care system for inflammatory disease along with the precise comprehension for autoinflammatory disease.

Research Products

• [Journal Article] Somatic NLRP3 mosaicism in Muckle-Wells syndrome. A genetic mechanism shared by different phenotypes of cryopyrin-associated periodic syndromes. (2014)
  • Author(s): Nakagawa K, Kawai T, Umebayashi H, Takei S, Kobayashi N, Yashiro M, Kubota T, Koike R, Akuta N, Shimoyama K, Iwata N, Saito MK, Ohara O, Kambe N, Yasumi T, Izawa K, Kawai T, Heike T, Yagüe J, Nishikomori R, Aróstegui JI et al.
  • Journal Title: Ann Rheum Dis. Volume: in press Issue: 3 Pages: 1-8
  • DOI: 10.1136/annrheumdis-2013-204361
  • Peer Reviewed / Open Access
• [Journal Article] A nationwide survey of Aicardi-Goutières syndrome patients identifies a strong association between dominant TREX1 mutations and chilblain lesions: Japanese cohort study. (2014)
  • Author(s): Abe J, Nakamura K, Nishikomori R, Kato M, Mitsuiki N, Izawa K, Awaya T, Kawai T, Yasumi T, Toyoshima I, Hasegawa K, Ohshima Y, Hiragi T, Sasahara Y, Suzuki Y, Kikuchi M, Osaka H, Ohya T, Ninomiya S, Fujikawa S, Akasaka M, Iwata N, Kawakita A, Funatsuka M, Shintaku H, Ohara O, Ichinose H, Heike T.
  • Journal Title: Rheumatology Volume: 53 Issue: 3 Pages: 448-458
  • DOI: 10.1093/rheumatology/ket372
  • Peer Reviewed
• [Journal Article] Somatic NLRP3 mosaicism in Muckle-Wells syndrome. A genetic mechanism shared by different phenotypes of cryopyrin-associated periodic syndromes. (2013)
  • Author(s): Nakagawa K, Gonzalez-Roca E, Souto A, Kawai T, Umebayashi H, Campistol JM, Cañellas J, Takei S, Kobayashi N, Callejas-Rubio JL, Ortego-Centeno N, Ruiz-Ortiz E, Rius F, Anton J, Iglesias E, Jimenez-Treviño S, Vargas C, Fernandez-Martin J, Calvo I, Hernández-Rodríguez J, Mendez M, Dordal MT, Basagaña M, Bujan S, Yashiro M, Kubota T, Koike R, Akuta N, Shimoyama K, Iwata N, Saito MK, Ohara O, Kambe N, Yasumi T, Izawa K, Kawai T, Heike T, Yagüe J, Nishikomori R, Aróstegui JI
  • Journal Title: Ann Rheum Dis
• [Journal Article] Obvious optic disc swelling in a patient with cryopyrin-associated periodic syndrome (2013)
  • Author(s): Kawai M, Yoshikawa T, Nishikomori R, Heike T, Takahashi K
  • Journal Title: Clin Ophthalmol Volume: 7 Pages: 1581-1585
• [Journal Article] Safety and efficacy of canakinumab in Japanese patients with phenotypes of cryopyrin-associated periodic syndrome as established in the first open-label, phase-3 pivotal study (24-week results) (2013)
  • Author(s): Imagawa T, Nishikomori R, Takada H, Takeshita S, Patel N, Kim D, Lheritier K, Heike T, Hara T, Yokota S
  • Journal Title: Clin Exp Rheumatol Volume: 31 Pages: 302-309
• [Journal Article] Guidance on the use of canakinumab in patients with cryopyrin-associated periodic syndrome in Japan (2013)
  • Author(s): Yokota S, Nishikomori R, Takada H, Kikuchi M, Nozawa T, Kanetaka T, Kizawa T, Miyamae T, Mori M, Heike T, Hara T, Imagawa T
  • Journal Title: Mod Rheumatol Volume: 23 Pages: 425-429
  • NAID: 10031175900
• [Journal Article] Detection of base substitution-type somatic mosaicism of the NLRP3 gene with >99. 9% statistical confidence by massively parallel sequencing (2012)
  • Author(s): Izawa K, Hijikata A, Tanaka N, Kawai T, Saito MK, Goldbach-Mansky R, Aksentijevich I, Yasumi T, Nakahata T, Heike T, Nishikomori R, Ohara O
  • Journal Title: DNA Res Volume: 19 Pages: 143-152
• [Journal Article] Induced pluripotent stem cells from CINCA syndrome patients as a model for dissecting somatic mosaicism and drug discovery (2012)
  • Author(s): Tanaka T, Takahashi K, Yamane M, Tomida S, Nakamura S, Oshima K, Niwa A, Nishikomori R, Kambe N, Hara H, Mitsuyama M, Morone N, Heuser JE, Yamamoto T, Watanabe A, Sato-Otsubo A, Ogawa S, Asaka I, Heike T, Yamanaka S, Nakahata T, Saito MK
  • Journal Title: Blood Volume: 120 Pages: 1299-1308
• [Journal Article] An approach to the patients with cryopyrin-associated periodic syndrome (CAPS) : a new biologic response modifier, canakinumab (2012)
  • Author(s): Yokota S, Kikuchi M, Nozawa T, Kizawa T, Kanetaka T, Miyamae T, Mori MA, Nishikomori R, Takata H, Heike T, Hara T, Imagawa T
  • Journal Title: Nihon Rinsho Meneki Gakkai Kaishi Volume: 35 Pages: 23-29
  • NAID: 10030465541
• [Journal Article] Detection of base substitution-type somatic mosaicism of the NLRP3 gene with >99.9% statistical confidence by massively parallel sequencing (2012)
  • Author(s): Izawa K
  • Journal Title: DNA Re Volume: 19 Pages: 143-152
  • Peer Reviewed
• [Journal Article] Heterozygous TREX1 p.Asp18Asn mutation can cause variable neurological symptoms in a family with Aicardi-Goutieres syndrome/familial chilblain lupus. (2012)
  • Author(s): Abe J
  • Journal Title: Rheumatology Volume: 52 Issue: 2 Pages: 406-408
  • DOI: 10.1093/rheumatology/kes181
  • Peer Reviewed
• [Journal Article] Hyperimmunoglobulinemia D and periodic fever syndrome (2011)
  • Author(s): Sakai H, Heike T
  • Journal Title: Nihon Rinsho Meneki Gakkai Kaishi Volume: 34 Pages: 382-387
  • NAID: 10029898019
• [Journal Article] High incidence of NLRP3 somatic mosaicism in patients with chronic infantile neurologic, cutaneous, articular syndrome (2011)
  • Author(s): Tanaka N, Izawa K, Saito MK, Sakuma M, Oshima K, Tanaka N, Izawa K, Saito MK, Sakuma M, Oshima K, Ohara O, Nishikomori R, Morimoto T, Kambe N, Goldbach-Mansky R, Aksentijevich I, de Saint Basile G, Neven B, van Gijn M, Frenkel J, Aróstegui JI, Yagüe J, Merino R, Ibañez M, Pontillo A, Takada H, Imagawa T, Kawai T, Yasumi T, Nakahata T, Heike T
  • Journal Title: International Multicenter Collaborative Study Volume: 63 Pages: 3625-3632
• [Journal Article] Patient with neonatal-onset chronic hepatitis presenting with mevalonate kinase deficiency with a novel MVK gene mutation (2011)
  • Author(s): Tahara M, Sakai H, Nishikomori R, Yasumi T, Heike T, Nagata I, Inui A, Fujisawa T, Shigematsu Y, Nishijima K, Kuwakado K, Watabe S, Kameyama J
  • Journal Title: Mod Rheumatol Volume: 21 Pages: 641-645
  • NAID: 10030206205
• [Journal Article] High incidence of NLRP3 somatic mosaicism in patients with chronic infantile neurologic, cutaneous, articular syndrome (2011)
  • Author(s): Tanaka N, Izawa K, Saito MK, Sakuma M, Oshima K, Ohara O, Nishikomori R, Morimoto T, Kambe N, Goldbach-Mansky R, Aksentijevich I, de Saint Basile G, Neven B, van Gijn M, Frenkel J, Arostegui JI, Yague J, Merino R, Ibanez M, Pontillo A, Takada H, Imagawa T
  • Journal Title: Arthritis Rheum Volume: 63 Issue: 11 Pages: 3625-32
  • DOI: 10.1002/art.30512
  • Peer Reviewed
• [Presentation] 自己炎症性疾患の包括的把握に向けた臨床研究体制の整備について (2013)
  • Author(s): 平家俊男
  • Organizer: 第116回日本小児科学会学術集会
  • Place of Presentation: 広島
  • Year and Date: 2013-04-20
• [Presentation] 自己炎症性疾患における診療研究の新展開～"炎症"と小児発熱性疾患～ (2013)
  • Author(s): 平家俊男
  • Organizer: 第117回日本小児科学会学術集会
  • Place of Presentation: 名古屋
  • Year and Date: 2013-04-12
• [Presentation] 自己炎症性疾患の包括的把握に向けた臨床研究体制の整備について (2013)
  • Author(s): 平家俊男
  • Organizer: 日本小児科学会学術集会シンポジウム
  • Place of Presentation: 広島
  • Invited
• [Presentation] 患者特異的iPS細胞を用いたCINCA症候群体細胞モザイクの病態解明 (2011)
  • Author(s): 田中孝之、平家俊男, 他
  • Organizer: 第21回日本小児リウマチ学会総会・学術集会
  • Place of Presentation: 神戸国際会議場
  • Year and Date: 2011-10-16
• [Book] 自己炎症性疾患・自然免疫不全症とその近縁疾患 (2012)
  • Author(s): 平家俊男, 他
  • Publisher: 診断と治療社
• [Remarks]
  • URL: http://aid.kazusa.or.jp/2013/