ダイヤモンド・ブラックファン貧血の新規分子病態の解明と治療法の開発

• 研究課題/領域番号: 23591554
• 研究種目: 基盤研究(C)
• 配分区分: 基金
• 応募区分: 一般
• 研究分野: 小児科学
• 研究機関: 日本医科大学
• 研究代表者: 三宅 弘一 日本医科大学, 医学部, 准教授 (90267211)
• 研究期間 (年度): 2011 – 2013
• 研究課題ステータス: 完了 (2013年度)
• 配分額: 5,070千円 (直接経費: 3,900千円、間接経費: 1,170千円); 2013年度: 1,560千円 (直接経費: 1,200千円、間接経費: 360千円); 2012年度: 1,560千円 (直接経費: 1,200千円、間接経費: 360千円); 2011年度: 1,950千円 (直接経費: 1,500千円、間接経費: 450千円)
• キーワード: リボゾーム蛋白 / 貧血 / 先天異常 / 先天性貧血 / siRNA / Diamond-Blackfan anemia / 遺伝子治療

研究概要

ダイアモンド・ブラックファン貧血(DBA)の病因としてDBA患者の約25%においてリボゾーム蛋白S19の遺伝 子異常が報告されているがいまだ完全には解明されていない。近年新たに他のリボゾーム蛋白(RPL5, RPL11, RPS24, RPS17)の異常が報告されており、これらの蛋白を抑制するレンチウイルスベクターを作製し、DBAモデル細胞の作製を行った。DBAモデル動物作製の為に、KRAB(Kruppel-associated box)遺伝子を組み込んだトランスジェニックマウスの作製を行った。

研究成果

• [雑誌論文] siRNA Knockdown of Tissue Inhibitor of Metalloproteinase-1 in Keloid Fibroblasts Leads to Degradation of Collagen Type I (2014)
  • 著者名/発表者名: Aoki M, Miyake K, Ogawa R, Dohi T, Akaishi S, Hyakusoku H, Shimada T
  • 雑誌名: J Invest Dermatol 巻: 134 ページ: 818-826
  • 査読あり
• [雑誌論文] miR-7a alleviates the maintenance of neuropathic pain through regulation of neuronal excitability (2014)
  • 著者名/発表者名: Sakai A, Saitow F, Miyake N, Miyake K, Shimada T, Suzuki H
  • 雑誌名: Brain 巻: 136 ページ: 2738-2750
  • 査読あり
• [雑誌論文] Mutant Ataxin-3 with an Abnormally Expanded Polyglutamine Chain Disrupts Dendritic Development and Metabotropic Glutamate Receptor Signaling in Mouse Cerebellar Purkinje Cells (2014)
  • 著者名/発表者名: Konno A, Shuvaev AN, Miyake N, Miyake K, Iizuka A, Matsuura S, Huda F, Nakamura K, Yanagi S, Shimada T, Hirai H
  • 雑誌名: Cerebellum 巻: 13 ページ: 29-41
  • 査読あり
• [雑誌論文] Cyclical mechanical stretch enhances degranulation and IL-4 secretion in RBL-2H3 mast cells (2014)
  • 著者名/発表者名: komiyama H, Miyake K, Asai K, Mizuno K, Shimada T
  • 雑誌名: Cell Biochemistry & Function 巻: 32 ページ: 70-76
  • 査読あり
• [雑誌論文] Cyclical mechanical stretch enhances degranulation and IL-4 secretion in RBL-2H3 mast cells (2014)
  • 著者名/発表者名: Komiyama H, Miyake K, Asai K, Mizuno K, Shimada T.
  • 雑誌名: Cell Biochem Funct. 巻: 32 号: 1 ページ: 70-76
  • DOI: 10.1002/cbf.2973
  • 査読あり
• [雑誌論文] Mutant ataxin-3 with an abnormally expanded polyglutamine chain disrupts dendritic development and metabotropic glutamate receptor signaling in mouse cerebellar purkinje cells (2014)
  • 著者名/発表者名: Konno A, Shuvaev AN, Miyake N, Miyake K, Iizuka A, Matsuura S, Huda F, Nakamura K, Yanagi S, Shimada T, Hirai H.
  • 雑誌名: Cerebellum 巻: 13 号: 1 ページ: 29-41
  • DOI: 10.1007/s12311-013-0516-5
  • 査読あり
• [雑誌論文] siRNA Knockdown of Tissue Inhibitor of Metalloproteinase-1 in Keloid Fibroblasts Leads to Degradation of Collagen Type I (2014)
  • 著者名/発表者名: Aoki M, Miyake K, Ogawa R, Dohi T, Akaishi S, Hyakusoku H, Shimada T.
  • 雑誌名: J Invest Dermatol. 巻: 134 号: 3 ページ: 818-826
  • DOI: 10.1038/jid.2013.396
  • 査読あり
• [雑誌論文] Direct Comparison of Administration Routes for AAV8-mediated Ocular Gene Therapy (2013)
  • 著者名/発表者名: Igarashi T, Miyake K, Asakawa N, Miyake N, Shimada T, Takahashi H.
  • 雑誌名: Curr Eye Res 巻: 38 ページ: 569-577
  • 査読あり
• [雑誌論文] Team-based Learning Using an Audience Response System : A Possible New Strategy for Interactive Medical Education (2013)
  • 著者名/発表者名: Fujikura T, Takeshita T, Homma H, Adachi K, Miyake K, Kudo M, Takizawa T, Nagayama H, Hirakawa K
  • 雑誌名: J Nippon Med Sch 巻: 80 ページ: 63-69
  • NAID: 130004147207
  • 査読あり
• [雑誌論文] Direct comparison of administration routes for AAV8-mediated ocular gene therapy (2013)
  • 著者名/発表者名: Igarashi T, Miyake K, Asakawa N, Miyake N, Shimada T, Takahashi H.
  • 雑誌名: Curr Eye Res. 巻: 38 号: 5 ページ: 569-577
  • DOI: 10.3109/02713683.2013.779720
  • 査読あり
• [雑誌論文] Role of survivin in acute lung injury: Epithelial cells of mice and humans (2013)
  • 著者名/発表者名: Terasaki Y, Terasaki M, Urushiyama H, Nagasaka S,Kungi S, et al.
  • 雑誌名: Lab Invest 巻: 93 号: 10 ページ: 1147
  • DOI: 10.1038/labinvest.2013.103
  • 査読あり
• [雑誌論文] miR-7a alleviates the maintenance of neuropathic pain through regulation of neuronal excitability (2013)
  • 著者名/発表者名: Sakai A, Saitow F, Miyake N, Miyake K, Shimada T, Suzuki H.
  • 雑誌名: Brain 巻: 136 号: 9 ページ: 2738-2750
  • DOI: 10.1093/brain/awt191
  • 査読あり
• [雑誌論文] Serotype-independent method of recombinant adeno-associated virus (AAV) vector production and purification (2012)
  • 著者名/発表者名: Miyake K, Miyake N, Yamazaki Y, Shimada T, Hirai Y.
  • 雑誌名: J Nippon Med Sch 巻: 79 ページ: 394-402
  • NAID: 130004057397
  • 査読あり
• [雑誌論文] Induction of cardiomyocyte-like cells in infarct hearts by gene transfer of gata4, mef2c, and tbx5 (2012)
  • 著者名/発表者名: Inagawa K, Miyamoto K, Yamakawa H, Muraoka N, Sadahiro T, Umei T, Wada R, Katsumata Y, Kaneda R, Nakade K, Kurihara C, Obata Y, Miyake K, Fukuda K, Ieda M.
  • 雑誌名: Circ Res 巻: 111 ページ: 1147-1156
  • 査読あり
• [雑誌論文] Successful gene therapy in utero for lethal murine hypophosphatasia (2012)
  • 著者名/発表者名: Sugano H, Matsumoto T, Miyake K, Watanabe A, Iijima O, Migita M, Narisawa S, Millán JL, Fukunaga Y, Shimada T.
  • 雑誌名: Hum Gene Ther 巻: 23 ページ: 399-406
  • 査読あり
• [雑誌論文] AAV-8 vector expressing IL-24 efficiently suppresses tumor growth mediated by specific mechanisms in MLL/AF4-positive ALL model mice (2012)
  • 著者名/発表者名: Tamai H, Miyake K, Yamaguchi H Takatori M, Dan K, Inokuchi K, Shimada T.
  • 雑誌名: Blood 巻: 119 ページ: 64-71
  • 査読あり
• [雑誌論文] Serotype-independent Method of Recombinant Adeno-associated. Virus (AAV) Vector Production and Purification (2012)
  • 著者名/発表者名: Miyake K, Miyake N, Yamazaki Y, Shimada T, Hirai Y
  • 雑誌名: J Nippon Med Sch 巻: 79 ページ: 394-402
  • NAID: 130004057397
  • 査読あり
• [雑誌論文] Induction of Cardiomyocyte-like Cells in Infarct Hearts by Gene Transfer of Gata4, Mef2c, and Tbx5 (2012)
  • 著者名/発表者名: Inagawa K, Miyamoto K, Yamakawa H, Muraoka N, Sadahiro T, Umei T, Wada R, Katsumata Y, Kaneda R, Nakade K, Kurihara C, Obata Y, Miyake K, Fukuda K, Ieda M
  • 雑誌名: Circulation research 巻: 111 号: 9 ページ: 1147-56
  • DOI: 10.1161/circresaha.112.271148
  • 査読あり
• [雑誌論文] AAV-8 vector expressing IL-24 efficiently suppresses tumor growth mediated by specific mechanisms in MLL/AF4-positive ALL model mice. (2012)
  • 著者名/発表者名: Tamai, H.
  • 雑誌名: Blood 巻: 119 号: 1 ページ: 64-71
  • DOI: 10.1182/blood-2011-05-354050
  • 査読あり
• [雑誌論文] Resistance of MLL-AFF1-positive acute lymphoblastic leukemia to tumor necrosis factor-alpha is mediated by S100A6 up-regulation (2011)
  • 著者名/発表者名: Tamai H, Miyake K, Yamaguchi H Takatori M, Dan K, Inokuchi K, Shimada T.
  • 雑誌名: Blood Cancer Journal 巻: 1
  • 査読あり
• [雑誌論文] Importance of c-kit mutation detection method sensitivity in prognostic analyses of t(8;21)(q22;q22) acute myeloid leukemia (2011)
  • 著者名/発表者名: Wakita S, Yamaguchi H, Miyake K, Mitamura Y, Kosaka F, Dan K, Inokuchi K.
  • 雑誌名: Leukemia 巻: 25 ページ: 1423-32
  • 査読あり
• [雑誌論文] Parkin-mediated protection of dopaminergic neurons in a chronic MPTP-minipump mouse model of Parkinson disease (2011)
  • 著者名/発表者名: Yasuda T, Hayakawa H, Nihira T, Ren YR, Nakata Y, Nagai M, Hattori N, Miyake K, Takada M, Shimada T, Mizuno Y, Mochizuki H.
  • 雑誌名: J Neuropathol Exp Neurol 巻: 70 ページ: 686-97
  • 査読あり
• [雑誌論文] Activated K-Ras protein accelerates human MLL/AF4-induced leukemo-lymphomogenicity in a transgenic mouse model (2011)
  • 著者名/発表者名: Tamai H, Miyake K, Takatori M, Miyake N Yamaguchi H, Dan K, Shimada T, Inokuchi K.
  • 雑誌名: Leukemia 巻: 25 ページ: 888-91
  • 査読あり
• [雑誌論文] Direct comparison of four adeno-associated virus serotypes in mediating the production of antiangiogenic proteins in mouse muscle (2011)
  • 著者名/発表者名: Isotani M, Miyake K, Miyake N, Hirai Y, Shimada T.
  • 雑誌名: Cancer Invest 巻: 29(5) ページ: 353-359
  • 査読あり
• [雑誌論文] Direct Comparison of Four Adeno-Associated Virus Serotypes in Mediating the Production of Antiangiogenic Proteins in Mouse Muscle (2011)
  • 著者名/発表者名: Mayu Isotani, Koichi Miyake, Noriko Miyake, Yukihiko Hirai, Takashi Shimada
  • 雑誌名: Cancer Investigation 巻: 29 号: 5 ページ: 353-359
  • DOI: 10.3109/07357907.2011.584585
  • 査読あり
• [学会発表] Successful Treatment of Adult MLD Model Mice By Intravenous Injection of Self-Complementary Type 9 AAV Vector Expressing ASA (2014)
  • 著者名/発表者名: Miyake N, Miyake K, Yamamoto M and Shimada T.
  • 学会等名: 17th Annual Meeting of the American Society of Gene & Cell Therapy
  • 発表場所: Washington DC
• [学会発表] Minimally invasive gene therapy of MLD model mice by intrathecal and intravenous injection of AAV9 vector (2014)
  • 著者名/発表者名: Miyake N, Miyake K, and Shimada T.
  • 学会等名: 10th WORLDSymposium™
  • 発表場所: San Diego,CA
• [学会発表] Minimally invasive gene therapy of MLD model mice by intrathecal and intravenous injection of AAV9 vector (2014)
  • 著者名/発表者名: Miyake N, Miyake K, Shimada T.
  • 学会等名: 10th WORLDSymposium™ 2014
  • 発表場所: San Diego, CA, USA
• [学会発表] Adeno−Associated Vector (Type 8)−Mediated Expression of siRNA Targeting Vascular Endothelial Growth Factor Efficiently Inhibits Neovascularization in a Murine Choroidal Neovascularization Model (2013)
  • 著者名/発表者名: Igarashi T, Miyake K, Miyake N, Iijima O, Yaguchi C, Shimada T and Takahashi H.
  • 学会等名: 16th Annual Meeting of the American Society of Gene & Cell Therapy
  • 発表場所: Salt Lake City, Utah
• [学会発表] Long−Term Secretion of Arylsulfatase A without Antibody Formation after AAV Mediated Neonatal Gene Transfer into MLD Model Mice (2013)
  • 著者名/発表者名: Miyake N, Miyake K, Yamamoto M and Shimada T.
  • 学会等名: 16th Annual Meeting of the American Society of Gene & Cell Therapy
  • 発表場所: Salt Lake City, Utah
• [学会発表] Adeno－Associated Vector (Type 8)－Mediated Expression of siRNA Targeting Vascular Endothelial Growth Factor Efficiently Inhibits Neovascularization in a Murine Choroidal Neovascularization Model (2013)
  • 著者名/発表者名: Igarashi T, Miyake K, Miyake N, Iijima O, Yaguchi C, Shimada T, Takahashi H.
  • 学会等名: 16th Annual Meeting of the American Society of Gene & Cell Therapy
  • 発表場所: Salt Lake City, Utah, USA
• [学会発表] Long－Term Secretion of Arylsulfatase A without Antibody Formation after AAV Mediated Neonatal Gene Transfer into MLD Model Mice (2013)
  • 著者名/発表者名: Miyake N, Miyake K, Yamamoto M, Shimada T.
  • 学会等名: 16th Annual Meeting of the American Society of Gene & Cell Therapy
  • 発表場所: Salt Lake City, Utah, USA
• [学会発表] Targeted Gene Transfer into the Ependymal Cells and Long-Term Enzyme Replacement in the CSF by Intraventricular Injection of AAV Vector Serotype 1 (2013)
  • 著者名/発表者名: Yamazaki Y, Hironaka K, Hirai Y, Miyake K, Shimada T.
  • 学会等名: 16th Annual Meeting of the American Society of Gene & Cell Therapy
  • 発表場所: Salt Lake City, Utah, USA
• [学会発表] siRNA Targeting Vascular Endothelial Growth Factor by adeno-associated vector (type 8) efficiently inhibits Neovascularization in a Murine Choroidal Neovascularization Model (2013)
  • 著者名/発表者名: Igarashi T, Miyake N, Iijima O, Yaguchi C, Shimada T, Takahashi H, Miyake K.
  • 学会等名: The 19th Annual Meeting of Japan Society of Gene Therapy
  • 発表場所: Okayama,Japan
• [学会発表] Tolerance induction to arylsulfatase A by AAV mediated neonatal gene transfer into MLD model mice (2013)
  • 著者名/発表者名: Miyake N, Miyake K, Yamamoto M, Shimada T.
  • 学会等名: The 19th Annual Meeting of Japan Society of Gene Therapy
  • 発表場所: Okayama, Japan
• [学会発表] AAV9 mediated gene therapy of MLD model mice (2012)
  • 著者名/発表者名: Miyake N, Miyake K, Sakai A, Yamamoto M, Endo A, Suzuki H, and Shimada T.
  • 学会等名: 20th Annual Meeting of the European Society of Gene & Cell Therapy
  • 発表場所: Versailles, France
• [学会発表] Gene therapy of adult MLD model mice by intrathecal administration of type 9 AAV vector (2012)
  • 著者名/発表者名: Miyake N, Miyake K, Sakai A, Yamamoto M, Endo A, Suzuki H, and Shimada T.
  • 学会等名: 15th Annual Meeting of the American Society of Gene & Cell Therapy
  • 発表場所: Philadelphia, Pennsylvania
• [学会発表] Gene therapy of adult MLD model mice by intrathecal administration of type 9 AAV vector (2012)
  • 著者名/発表者名: Miyake N, Miyake K, Sakai A, Yamamoto M, Endo A, Suzuki H, Shimada T
  • 学会等名: 15th Annual Meeting of the American Society of Gene & Cell Therapy
  • 発表場所: Philadelphia, USA
• [学会発表] Successful gene therapy in utero for lethal murine hypophosphatasia (2012)
  • 著者名/発表者名: Sugano H, Miyake K, Watanabe A, Iijima O, Narisawa S, Millán JL, Fukunaga Y, Shimada T
  • 学会等名: 6th Alkaline Phosphatasie and Hypophosphatasia International Symposium
  • 発表場所: Huningue, France
• [学会発表] Ex vivo gene therapy of severe infantile hypophosphatasia model mice using lentiviral transduced bone marrow cells (2012)
  • 著者名/発表者名: Iijima O, Sugano H, Watanabe A, Miyake K, Shimada T
  • 学会等名: 6th Alkaline Phosphatasie and Hypophosphatasia International Symposium
  • 発表場所: Huningue, France
• [学会発表] Ex vivo gene therapy of severe infantile hypophosphatasia model mice using lentiviral transduced bone marrow cells (2012)
  • 著者名/発表者名: Iijima O, Sugano H, Watanabe A, Miyake K, Shimada T
  • 学会等名: The 18th Annual Meeting of Japan Society of Gene Therapy
  • 発表場所: 熊本
• [学会発表] Successful treatment of adult MLD model mice by intrathecal administration of type 9 AAV vector (2012)
  • 著者名/発表者名: Miyake N, Miyake K, Sakai A, Yamamoto M, Endo A, Suzuki H, Shimada T
  • 学会等名: The 18th Annual Meeting of Japan Society of Gene Therapy
  • 発表場所: 熊本
• [学会発表] DRG神経におけるmiR-7a過剰発現は神経障害性疼痛を特異的に抑制する (2012)
  • 著者名/発表者名: 坂井敦、齋藤文仁、三宅紀子、三宅弘一、島田隆、鈴木秀典
  • 学会等名: 第35回日本神経科学大会
  • 発表場所: 名古屋
• [学会発表] 骨髄細胞移植による低フォスファターゼ症のex vivo遺伝子治療 (2012)
  • 著者名/発表者名: 飯島修、菅野華子、鹿子田千津、渡邉淳、三宅弘一、島田隆
  • 学会等名: 第57回日本人類遺伝学会学術集会
  • 発表場所: 東京
• [学会発表] Gene therapy of adult MLD model mice by intrathecal administration of type 9 AAV vector (2012)
  • 著者名/発表者名: Miyake N, Miyake K, Sakai A, Yamamoto M, Endo A, Suzuki H, Shimada T
  • 学会等名: 第4回国際ライソゾーム病フォーラム・第17回日本ライソゾーム病研究会
  • 発表場所: 東京
• [学会発表] Rescue of lethal hypophosphatasia mice by neonatal ex vivo gene therapy using lentivirally transduced bone marrow cells (2012)
  • 著者名/発表者名: Iijima O, Miyake K, Sugano H, Tsutomu I, Chizu K, Watanabe A, Shimada T
  • 学会等名: 54th American Society of Hematology Annual Meeting and Exposition
  • 発表場所: Atlanta, USA
• [学会発表] Intrathecal Administration of Type 9 AAV Vector Expressing Arylsulfatase A Is Effective for Reduction of Sulfatide Storage but Not for Correction of Neurological Deficits in Adult Metachromatic Leukodystrophy Model Mice with Overt Neurological Symptoms (2011)
  • 著者名/発表者名: Miyake N, Miyake K, Sakai A, Yamamoto M, Endo A, Suzuki H, and Shimada T.
  • 学会等名: 14th Annual Meeting of the American Society of Gene & Cell Therapy
  • 発表場所: Seattle, WA
• [学会発表] Development of cell targeting strategy using HIV vector pseudtyped with HIV envelope (2011)
  • 著者名/発表者名: Koichi Miyake, Takashi Shimada
  • 学会等名: The 17th Annual Meeting of Japan Society of Gene Therapy
  • 発表場所: 福岡
• [図書] Development of Muscle-Directed Systemic Cancer Gene Therapy. Novel Gene Therapy Approaches (2013)
  • 著者名/発表者名: Miyake K, Shimada T
  • 出版者: Edited by Ming Wei and David Good, Published by InTech
• [図書] Novel Gene Therapy Approaches (2013)
  • 著者名/発表者名: Miyake K, Shimada T
  • 総ページ数: 450
  • 出版者: InTech
• [図書] Development and Application of HIV Vectors Pseudotyped with HIV Envelopes. Viral Gene Therapy (2011)
  • 著者名/発表者名: Miyake K, Shimada T
  • 出版者: Edited by Ke Xu, Published by InTech
• [図書] Viral gene therapy (2011)
  • 著者名/発表者名: Koichi Miyake, Takashi Shimada
  • 総ページ数: 16
  • 出版者: Intec