国立研究開発法人 国立成育医療研究センター National Center for Child Health and Development

代表: 03-3416-0181 / 予約センター(病院): 03-5494-7300
〈月~金曜日(祝祭日を除く)9時〜17時〉

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研究者・企業の方へ Scholar & Enterprise

研究者・企業の方へ Scholar & Enterprise

成育遺伝研究部

研究部紹介

小児の難治性遺伝性疾患に関わる原因遺伝子を同定し、その機能を解析することで遺伝子ベースでの新たな治療法の開発を目指しています。具体的には、疾患iPS細胞の樹立とその解析ならびに臨床用ベクターの開発を行っており、これらの研究結果の下に遺伝子治療臨床研究を準備しています。
特に原発性免疫不全症に対する、次世代シークエンサーを用いた遺伝子解析と疾患特異的iPS細胞を用いた病態解析による網羅的相補的遺伝子診断法(comprehensive complimentary diagnosis: CCD)の開発や新規治療法としての造血幹細胞遺伝子治療の実施は、当センター病院と一体となって進めている主要な研究テーマです。


研究内容

○原発性免疫不全症への遺伝子治療の確立

  1. X連鎖慢性肉芽腫症に対するレトロウイルスベクターによる遺伝子治療を米国国立衛生研究所(NIH)との共同研究にて行っています。
  2. Wiskott-Aldrich症候群やX連鎖重症複合免疫不全症に対してレンチウイルスベクターを用いた遺伝子治療の実施を準備しています。
  3. 遺伝子治療臨床研究の安全性を評価するため、臨床用ウイルスベクターの品質管理や遺伝子治療用ベクターの染色体挿入部位解析を次世代シークエンサーやdigital PCRを用いて行っています。

○疾患特異的iPS細胞の樹立

  1. 原発性免疫不全症や先天性代謝疾患などの小児難治性遺伝性疾患患者から採取した細胞(血液細胞や皮膚細胞)より、疾患特異的iPS細胞を樹立しています。
  2. 樹立したiPS細胞を用いて詳細な病態解析や遺伝子改変技術の研究を行っています。

○代謝疾患に対する遺伝子治療法の確立

Niemann-Pick病やムコ多糖症などのライソゾーム病を主な対象とし、アデノ随伴ウイルスベクターを用いた新規治療法の開発を行っています。

○ウイルスベクターに関する研究

  1. ヒト由来の転写抑制因子をクローニングし、レトロウイルスベクターの遺伝子発現抑制機構を解析しています。
  2. 将来の遺伝子治療臨床研究に向け、より安全で治療効果の高いウイルスベクターの開発を行っています。

○成育バイオバンク

小児難治性遺伝性疾患患者から得られたiPS細胞等を成育バイオバンクのバイオリソースとして保管し、創薬を含む今後の科学の発展に役立つバンク事業を目指しています。

○研究部問い合わせ窓口

小野寺雅史
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成育遺伝研究部

         

疾患遺伝子構造研究室

部室員

  • 安田 徹(研究員)

業績

2017

  1. Okuno M, Kasahara Y, Onodera M, Takubo N, Okajima M, Suga S, Watanabe N, Suzuki J, Ayabe T, Urakami T, Kawamura T, Kikuchi N, Yokota I, Kikuchi T, Amemiya S, Nakabayashi K, Hayashi K, Hata K, Matsubara Y, Ogata T, *Fukami M, Sugihara S. Nucleotide substitutions in CD101, the human homolog of a diabetes susceptibility gene in non-obese diabetic mouse, in patients with type 1 diabetes. Journal of Diabetes Investigation 8: 286-294, 2017.
  2. Osumi T, Kato M. Ouchi-Uchiyama M, Tomizawa D, Kataoka K, Fuji Y, Seki M, TAkita J, Ogawa S, Uchiyama T, Ohki K, Kiyokawa N. Blastic transformation of juvenile myelomonocytic leukemia caused by the copy number gain of onocogenic KRAS. Pediatr Blood Cancer 2017 doi: 10.1002/pbc.26496
  3. Goto F, Uchiyama T, Nakazawa Y, Kawai T, Imai K, Onodera M. Persistent impairment of T cell regeneration in a patient with activated PI3K d syndrome. J Clin Immunol. 2017 doi: 10.1007/s10875-017-0393-7

2016

  1. Ichida Y, Utsunomiya Y, Onodera M: Effect of the linkers between the zinc fingers in zinc finger protein 809 on gene silencing and nuclear localization. Biochemical and Biophysical Research Communications. 471: 533-538, 2016.
  2. Obayashi N, Arai K, Nakano N, Mizukami T, Kawai T, Yamamoto S, Shimizu H, Nunoi H, Shimizu T, Tang J, Onodera M: Leopard skin-like colonic mucosa: A novel endoscopic finding of chronic granulomatous disease-associated colits. Journal of Pediatric Gastroenterology and Nutrition. 62: 56-59, 2016.
  3. Ichida Y, Utsunomiya Y, Onodera M: The third to fifth zinc fingers play an essential role in the binding of ZFP809 to the MLV-derived PBS. Biochemical and Biophysical Research Communications. 469: 490-494, 2016.
  4. Choong CJ, Sasaki T, Hayakawa H, Yasuda T, Baba K, Hirata Y, Uesato S, Mochizuki H. A novel histone deacetylase 1 and 2 isoform-specific inhibitor alleviates experimental Parkinson's disease. Neurobiol Aging. 37:103-16 2016.
  5. Tomono T, Hirai Y, Okada H, Adachi K, Ishii A, Shimada T, Onodera M, Tamaoka A, *Okada T: Ultracentrifugation-free chromatography-mediated large-scale purification of recombinant adeno-associated virus serotype 1 (rAAV1). Molecular Therapy Methods and clinical Development. 3: 15058, 2016.
  6. Nagaya M, Watanabe M, Kobayashi M, Nakano K, Arai Y, Asano Y, Takeishi T, Umeki I, Fukuda T, Yashima S, Takayanagi S, Watanabe N, Onodera M, Matsunari H, Umeyama K, *Nagashima H. A transgenic-cloned pig model expressing non-fluorescent modified Plum. Journal of Reproduction and Development. 62; 511-520, 2016.
  7. Kawano Y, *Nakae J, Watanabe N, Kikuchi T, Tateya S, Tamori Y, Kaneko M, Abe T, Onodera M, Itoh H. Colonic Pro-Inflammatory Macrophages Cause Insulin Resistance in an Intestinal Ccl2/Ccr2-Dependent Manner. Cell Metabolism. 24: 295-310, 2016.
  8. Hasegawa K, Yasuda T, Shiraishi C, Fujiwara K, Przedborski S, Mochizuki H, Yoshikawa K. Promotion of mitochondrial biogenesis by necdin protects neurons against mitochondrial insults. Nat Commun. 14;7:10943, 2016.
  9. Ikawa Y, Uchiyama T, Jagadeesh GJ, *Candotti F. The long terminal repeat negative control region is a critical element for insertion oncogenesis after gene transfer into hematopoietic progenys with Moloney murine leukemia viral vectors. Gene therapy. 23:815-818. 2016.
  10. Naiki Y, Miyado M, Horikawa R, Katsumata N, Onodera M, Pang S, Ogata T, *Fukami M. Extra-adrenal induction of Cyp21a1 ameliorates systemic steroid metabolism in a mouse model of congenital adrenal hyperplasia. Endocrine Journal. 63: 897-904, 2016.

2015

  1. Nakazawa Y, Kawai T, Uchiyama T, Goto F, Watanabe N, Maekawa T, Ishigro A, Okuyama, T, Otsu M, Yamada M, Hershfield MS, Ariga T, Onodera M: Effects of enzyme replacement therapy on immune function in ADA deficiency patient. Clin Immunol 161: 391-393, 2015.
  2. Ichida Y, Utsunomiya Y, Yasuda T, Nakabayashi K, Sato T, Onodera M: Functional domains of ZFP809 essential for nuclear localization and gene silencing. PLOS ONE 10: e0139274, 2015.
  3. Ichida Y, Utsunomiya Y, Tomikawa J, Nakabayashi K, Sato T, Onodera M: Long time-course monitoring of ZFP809-mediated gene silencing in transgene expression driven by promoters containing MLV-derived PBS. Biosci Biotechnol Biochem 7:1-7, 2015.
  4. Kawai T, Arai K, Harayama S, Nakazawa Y, Goto F, Maekawa T, Tamura E, Uchiyama T, Onodera M: Severe and Rapid Progression in Very Early-Onset Chronic Granulomatous Disease-Associated Colitis. J Clin Immunol 35: 583-588, 2015.
  5. Yoshida W, Tomikawa J, Inaki M, Kimura H, Onodera M, Hata K, Nakabayashi K: An insulator element located at the cyclin B1 interacting protein 1 gene locus is highly conserved among mammalian species. PLOS ONE 10: e0131204, 2015.
  6. Takeuchi Y, Takeuchi E, Ishida T, Onodera M, Nakauchi H, Otsu M: Curative haploidentical BMT in a murine model of X-linked chronic granulomatous disease. Int J Hematol 102: 111-120, 2015.
  7. Watanabe M, Kobayashi1 M, Nagaya M, Matsunari H, Nakano K, Maehara M, Hayashida G, Takayanagi S, Sakai R, Umeyama K, Watanabe N, Onodera M, Nagashima H: Production of transgenic cloned pigs expressing the far-red fluorescent protein monomeric Plum. J. Reprod Dev 61: 169-177, 2015.
  8. Otsu M, Yamada M, Nakajima S, Kida M, Maeyama Y, Hatano N, Toita N, Takezaki S, Okura Y, Kobayashi R, Matsumoto Y, Tatsuzawa , Tsuchida F, Kato S, Kitagawa M, Mineno J, Hershfield MS, Bali P, Candotti F, Onodera M, Kawamura N, Sakiyama Y, Ariga T: Treatment Outcomes in Two Japanese Adenosine Deaminase-Deficiency Patients Treated by Stem Cell Gene Therapy with No Cytoreductive Conditioning. J Clin Immunol 35: 384-398, 2015.

2014

  1. Takeda K, Kawai T, Nakazawa Y, Komuro H, Yamamoto M, Shoji K, Morita K, Miyairi I, Katsuta T, Ohya Y, Ishiguro A, Onodera M: Augmentation of anti-tubercular therapy with interferon g in a patient with dominant partial interferon g. Clin. Immunol. 151: 25-28, 2014.
  2. Onuki K, Sugiyama H, Ishige K, Kawamoto T, Ota T, Ariizumi S, Yamato M, Kadota S, Takeuchi K, Ishikawa A, Onodera M, Onizawa K, Yamamoto M, Miyoshi E, Shoda J: Expression of N-acetylglucosaminyltransferase V in the subserosal layer correlates with postsurgical survival of pathological tumor stage 2 carcinoma of the gallbladder. J Gastroenterol 49:702-714, 2014.
  3. Akagi K, Kawai T, Watanabe N, Yokoyama M, Arai K, Harayama S, Oana S, Onodera M: A case of macrophage activation syndrome developing in a patient with chronic granulomatous disease-associated colitis. J Pediatr Hematol Oncol 36: e169-172, 2014.
  4. Lai CY, Yamazaki S, Okabe M, Suzuki S, Maeyama Y, Iimura Y, Onodera M, Kakuta S, Iwakura Y, Nojima M, Otsu M, Nakauchi H: Stage-specific roles for Cxcr4 signaling in murine hematopoietic stem/progenitor cells in the process of bone marrow repopulation. Stem Cells 32: 1929-1942, 2014.
  5. Looi CY, Sasahara Y, Watanabe Y, Satoh M, Hakozaki I, Uchiyama M, Wong WF, Du W, Uchiyama T, Kumaki S, Tsuchiya S, KureS. The open conformation of WASP regulates its nuclear localization and transcription in myeloid cells. Int Immunol. 26: 341-352, 2014
  6. Katsuya Y, Hojo M, Kawai S, Kawai T, Onodera M, Sugiyama H, Chronic granulomatous disease with pulmonary mass-like opacities secondary to hypersensitivity pneumonitis. J. Med. Case Rep.2014 Jul 2;8(1):242. 
  7. Shigeta T, Sakamoto S, Uchida H, Sasaki K, Hamano K, Kanazawa H, Fukuda A, Kawai T, Onodera M, Nakazawa A, Kasahara M: Basiliximab treatment for steroid-resistant rejection in pediatric patients with acute liver failure after liver transplantation. Pediatr. Transplant. 18: 860-867, 2014.
  8. Kawai T, Watanabe N, Yokoyama M, Nakazawa Y, Goto F, Uchiyama T, Higuchi M, Maekawa T, Tamura E, Nagasaka S, Hojo M, Onodera M.: Interstitial Lung Disease with Multiple Microgranulomas in Chronic Granulomatous Disease. J. Clin Immunol. 34: 933-940, 2014.
  9. Yamazaki Y, Yamada M, Kawai T, Morio T, Onodera M, Ueki M, Watanabe N, Takada H, Takezaki S, Chida N, Kobayashi I, Ariga T: Two Novel Gain-of-Function Mutations of STAT1 Responsible for Chronic Mucocutaneous Candidiasis Disease: Impaired Production of IL-17A and IL-22, and the Presence of anti-IL-17F Autoantibody. J. Immunol. 193: 48800-48807, 2014.
  10. Mori M, Onodera M, Morimoto A, Kosaka Y, Morio T, Notario GF Sharma S, Saji T: Palivizumab use in Japanese infants and children with immunocompromised conditions. Pediatr. Infect. Dis. J. 33: 1183-1185, 2014.

2013

  1. Kawai T, Watanabe N, Yokoyama M, Arai K, Oana S, Harayama S, Yasui K, Oh-ishi T, Onodera M: Thalidomide Attenuates Excessive Inflammation without Interrupting Lipopolysaccharide-driven Inflammatory Cytokine Production in Chronic Granulomatous Disease. Clin. Imunol. 2013;147:122-128
  2. Hamanaka S, Ooehara Jun, Morita Y, Ema H, Takahashi S, Miyawaki A, Otsu M, Yamaguchi T, Onodera M, Nakauchi H: Generation of transgenic mouse line expressing Kusabira Orange throughout body, including erythrocytes, by random segregation of provirus method. BBRC 2013;435:586-591
  3. Watanabe Y, Sasahara Y, Saoh M, Looi CY, Katayama S, Suzuki T, Suzuki N, Ouchi M, Horino S, Moriya K, Nanjyo Y, Onuma M, Kitazawa H, Irie M, Niizuma H, Uchiyama T, Rikiishi T, Kumaki S, Minegishi M, Wada T, Yachie A, Tsuchiya S, Kure S. A case series of CAEBV of children and young adults treated with reduced-intensity conditioning and allogeneic bone marrow transplantation: a single center study. Eur J Haematol. 2013;91:242-248
  4. Tornack J, Seiler K, Grützkau A, Grün JR, Onodera M, Melchers F, Tsuneto M: Ectopic runx1 expression rescues tal-1-deficiency in the generation of primitive and definitive hematopoiesis. PLoS One 2013;8(7):e70116
  5. Yamamoto R, Morita Y, Ooehara J, Hamanaka S, Onodera M, Rudolph KL, Ema H, Nakauchi H: Clonal analysis unveils self-renewing lineage-restricted progenitors generated directly from hematopoietic stem cells 2013;154:1112-1126
  6. Kobayashi M,Watanabe M, Matsunari H, Nakano K, Kanai T, Hayashida G, Matsumura Y, Kuramoto M, Sakai R, Arai Y, Umeyama K, Watanabe N, Onodera M, Nagaya M, Nagashima H: 20 generation and characterization of transgenic-cloned pigs expressing the far-red fluorescent protein monomeric plum. Reprod Fertil 2013;26:124-125
  7. Horino S, Uchiyama T, So T,Nagashima H, Sun SL, Sato M, Asao A, Haji Y, Sasahara Y, Candotti F, Tsuchiya S, Kure S, Sugamura K,Ishii: NGene therapy model of X-linked severe combined immunodeficiency using a modified foamy virus vector. PLos One 2013;8:e71594

2012

  1. Kawano Y, Nakae J, Watanabe N, Fujisaka S, Iskandar K, Sekioka R, Hayashi Y, Tobe K, Kasuga M, Noda T, Yoshimura A, Onodera M, Itoh H: Loss of PDK1-Foxo1 signaling in myeloid cells predisposes to adipose tissue inflammation and insulin resistance. Diabetes 61: 1935-1948, 2012.
  2. Imagawa T, Takei S, Umebayashi H, Yamaguchi K, Itoh Y, Kawai T, Iwata N, Murata T, Okafuji I, Miyoshi M, Onoe Y, Kawano Y, Kinjo N, Mori M, Mozaffarian N, Kupper H, Santra S, Patel G, Kawai S, and Yokota S: Efficacy, Pharmacokinetics, and Safety of Adalimumab in Pediatric Patients with Juvenile Idiopathic Arthritis in Japan. Clin Rheumatol 31: 1713-1721, 2012.
  3. Kawai T, Nishikomori R, Izawa K, Murata Y, Tanaka N, Sakai, H Saito M, Yasumi T, Takaoka Y, Nakahata T, Mizukami T, Nunoi H, Kiyohara Y, Yoden A, Murata T, Sasaki, S Ito E, Akutagawa H, Kawai T, Imai C, Okada, S Kobayashi M, Heike T: Frequent somatic mosaicism of NEMO in T cells of patients with X-linked anhidrotic ectodermal dysplasia with immunodeficiency. Blood 119: 5458-5466, 2012

2011

  1. Kawahara M, Chen J, Sogo T, Teng J, Otsu M, Onodera M, Nakauchi H, Ueda H, Nagamune T:Growth promotion of genetically modified hematopoietic progenitors using antibody/ c-Mpl chimera. Cytokine 55: 402-408, 2011.
  2. Maeyama Y, Otsu M, Kubo S, Yamano T, Iimura Y, Onodera M, Kondo S, Sakiyama Y, Ariga T: Intracellular estrogen receptor-binding fragment associated antigen 9 exerts in vivo tumor promoting effects via its coiled-coil region. Int J Oncology 39: 41-49, 2011.
  3. Fujisawa Y, Nabekura T, Kawachi Y, Otsuka F, Onodera M: Enforced ROR(gamma)t expression in haematopoietic stem cells increases regulatory T cell number, which reduces immunoreactivity and attenuates hypersensitivity in vivo. Asian Pac J Allergy Immunol 29: 86-93, 2011.
  4. Kunishima S, Kashiwagi H, Otsu M, Takayam N, Eto K, Onodera M, Miyajima Y, Takamatsu Y, Suzumiya J, Matsubara K, Tomiyama Y, S Hidehiko: Heterozygous ITGA2B R995W mutation inducing a constitutive activation of the aIIbb3 receptor affects proplatelet formation and causes congenital macrothrombocytopenia. Blood117: 5479-5484, 2011.
  5. Sugiyama H, Onuki K, Ishige K, Baba N, Ueda T, Matsuda S, Takeuchi K, Onodera M, Nakanuma Y, Yamato M, Yamamoto M, Hyodo I, Shoda J: Potent In Vitro and In Vivo Antitumor Activity of Sorafenib Against Human Intrahepatic Cholangiocarcinoma Cells. J Gastroenterol 46: 779-789, 2011.
  6. Kawai T, Kusakabe H, Seki A, Kobayashi S, Onodera M: Osteomyelitis due to triethoprim/sulfamethoxazole-resistant Edwardsiella tarda infection in a patient with X-linked chronic granulomatous disease. Infection 39: 171-173, 2011.

2010

  1. Tozuka Y, Kumon M, Wada E, Onodera M, Mochizuki H, Wada K: Material obesity impairs hippocampal BDNF production and spatial learning performance in young mouse offspring. Neurochem Int 57: 235-247, 2010.
  2. Hirata Y Hamanaka S, Onodera M: Transactivation of the dopamine receptor 3 gene by a single provirus integration results in development of B cell lymphoma in transgenic mice generated from retrovirally transduced embryonic stem cells. Blood115: 3930-3938, 2010.
  3. Miyamoto N, Tanaka R, Shimura H, Watanabe T, Mori H, Onodera M, Mochizuki H, Hattori N, Urabe T: Phosphodiesterase III inhibition promotes differentiation and survival of oligodendrocyte progenitors and enhances regeneration of ischemic white matter lesions in the adult mammalian brain. J Cereb Blood Flow Metab 30: 299-310, 2010.
  4. Kobayashi H, Shimada Y, Ikegami M, Kawai T, Sakurai K, Urashima T, Ijima M, Fujiwara M, Kaneshiro K, Ohashi T, Eto Y, Ishigaki K, Osawa M, Kyosen SO, Ida H: Prognostic factors for the late onset Pompe disease with enzyme replacement therapy: From our experience of 4 cases including an autopsy case. Mol Genet Metab100: 14-19, 2010.