ヒト赤芽球の脱核機序に関する研究

• Project/Area Number: 17659286
• Research Category: Grant-in-Aid for Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Hematology
• Research Institution: Akita University
• Principal Investigator: 澤田 賢一 Akita University, 医学部, 教授 (90226069)
• Co-Investigator(Kenkyū-buntansha): 高桑 雄一 東京女子医科大学, 医学部, 教授 (40113740)
• Project Period (FY): 2005 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥3,400,000 (Direct Cost: ¥3,400,000); Fiscal Year 2007: ¥700,000 (Direct Cost: ¥700,000); Fiscal Year 2006: ¥700,000 (Direct Cost: ¥700,000); Fiscal Year 2005: ¥2,000,000 (Direct Cost: ¥2,000,000)
• Keywords: ヒト赤芽球 / 脱核 / マクロファージ / centrosome / 4.1R / CD34 / 細胞質分裂 / 膜蛋白質 / 細胞骨格蛋白質 / 赤芽球 / 膜骨格 / 膜蛋白 / Glycophorin A / Cytokinesis

Research Abstract

本研究では、1)ヒト赤芽球の脱核に関与する赤芽球膜骨格蛋白の親和性と解離定数の制御機構、2)脱核に伴う細胞構造・膜骨格蛋白の赤血球内外への移行動態、3)造血幹・前駆細胞(CD34+細胞)から赤芽球系前駆細胞そして赤血球へと至る過程における構成蛋白質の代謝回転とその調節機構を解析することを目的とした。
本年度は上記1),2)の関連のもとに、ヒト赤芽球の脱核に関する研究を発展させた。その結果、以下を明らかにした。
1)ヒト赤芽球の脱核時間は8.4±3.4分
2)脱核率は1.16±0.42%/hourをピークとして以後は経時的に減少する
3)脱核はマクロファージなどの支持細胞の関与を必要としない
4)核の網赤血球からの完全分離にはずり応力やマクロファージによる核の貧食が必要である
5)脱核は細胞質分裂の一種である
6)脱核にcentrosomeは関与しない
以上の成果について現在投稿中である。
上記3)においては赤血球膜蛋白である4.1Rを中心に解析した。4.1Rは分子量135kDaと80kDaの二つのisoformからなり、赤芽球の分化過程でその発現が入れ替わるが、その機序は不明に留まっている。本研究では以下のことを明らかにした。
1)4.1R135は、赤芽球発生の初期段階から発現するが網赤血球には発現しない
2)4.1R80は4.1R135に遅れて発現し網赤血球にも発現する
3)4.1R80と4.1R135は膜骨格蛋白質に対する親和性と解離定数が異なる
以上の成果について現在投稿中である。

Research Products

• [Journal Article] Clinical features of adult acute leukemia with 11q23 abnormalities in Japan: multicenter co-operative study. (2008)
  • Author(s): Tamai, H., Yamaguchi, H., Hamaguchi, H., Yagasaki, F., Bessho, M., Kobayashi, T., Akiyama, H., Sakamaki, H., Takahashi, S., Tojo, A., Ohmine, K., Ozawa, K., Okumura, H., Nakao, S., Arai, A., Miura, O., Toyota, S., Gomi, S., Murai, Y., Usui, N., Miyazawa, K.,Ohyashiki,K.,Kato,A.,Oshimi,K.,Inokuchi,K.,Dan,K.
  • Journal Title: Int J Hematol 87 Pages: 195-202
  • Peer Reviewed
• [Journal Article] Long-Term response and outcome following immunosuppressive therapy in thymoma-associated pure red cell aplasia: a nationwide cohort study in Japan for the PRCA collaborative study group. (2008)
  • Author(s): Hirokawa, M., Sawada, K., Fujishima. N., Nakao, S., Urabe, A., Dan, K., Fujisawa, S., Yonemura, Y., Kawano, F., Omine, M., Ozawa, K. for the PRCA Collaborative Study Group.
  • Journal Title: Haematologica 93 Pages: 27-33
  • Peer Reviewed
• [Journal Article] Itraconazole oral solution enhanced vincristine neurotoxicity in five patients with malignant lymphoma. (2008)
  • Author(s): Takahashi, N., Kameoka, Y., Yamanaka, Y., Ubukawa, K., Saito, K., Fujishima, M., Fujishima, M., Saito, H., Hirokawa, M., Scott, S.A., Sawada, K.
  • Journal Title: Intern Med 47 Pages: 651-653
  • NAID: 130000080069
  • Peer Reviewed
• [Journal Article] Gene expression profiling of peripheral blood mononuclear cells from patients with minimal change nephrotic syndrome by cDNA microarrays. (2008)
  • Author(s): Komatsuda, A., Wakui, H., Iwamoto, K., Harada, M., Okamoto, Y. Sawada, K.
  • Journal Title: Am J Nephrol 28 Pages: 539-547
  • Peer Reviewed
• [Journal Article] Sulfasalazine-induced hypersensitivity syndrome and hemophagocytic syndrome associated with reactivation of Epstein-Barr virus. (2008)
  • Author(s): Komatsuda, A., Okamoto, Y., Hatakeyama, T., Wakui, H., Sawada, K.
  • Journal Title: Clin Rheumatol 27 Pages: 395-397
  • Peer Reviewed
• [Journal Article] Long-term outcome of patients with acquired primary idiopathic pure red cell aplasia receiving cyclosporine A. A nationwide cohort study in Japan for the PRCA collaborative study group. (2007)
  • Author(s): Sawada, K., Hirokawa, M., Fujishima, N., Teramura, M., Bessho, M., Dan, K., Tsurumi, H., Nakao, S., Urabe, A., Omine, M., Ozawa, K. for the PRCA collaborative study group.
  • Journal Title: Haematologica 92 Pages: 1021-1028
  • Peer Reviewed
• [Journal Article] Prolonged reactivation of cytomegalovirus infection following successful rituximab therapy for Epstein-Barr virus-associated posttransplantation lymphoproliferative disorder. (2007)
  • Author(s): Hirokawa, M., Kawabata, Y., Fujishima, N., Yoshioka, T., Sawada, K.
  • Journal Title: Int J Hematol 86 Pages: 291-292
  • NAID: 10019799002
  • Peer Reviewed
• [Journal Article] Up-regulation of TRAIL mRNA expression in peripheral blood mononuclear cells from patients with active systemic lupus erythematosus. (2007)
  • Author(s): Komatsuda, A., Wakui, H., Iwamoto, K., Togashi, M., Maki, N., Masai, R., Hatakeyama, T., Sawada, K.
  • Journal Title: Clin Immunol 125 Pages: 26-29
  • Peer Reviewed
• [Journal Article] Differences between myeloperoxidase-specific and -nonspecific P-ANCA-associated renal disease. (2007)
  • Author(s): Ohtani, H., Wakui, H., Komatsuda, A., Chyzh, K. A., Hatakeyama, T., Masai, R., Okuyama, S., Togashi, M., Sawada, K.
  • Journal Title: Ren Fail 29 Pages: 183-187
  • Peer Reviewed
• [Journal Article] Skewed T cell receptor repertoire of V δ 1+ γ δ T lymphocytes after human allogeneic heamatopoietic stem cell transplantation and the potential role for Epstein-Barr virus-infected B cells in clonal restriction. (2007)
  • Author(s): Fujishima, N., Hirokawa, M., Fujishima, M., Yamashita, J., Saitoh, H., Ichikawa, Y., Horiuchi, T., Kawabata, Y., Sawada, K.
  • Journal Title: Clin Exp Immunol 149 Pages: 70-79
  • Peer Reviewed
• [Journal Article] Adrenal insufficiency complicated with antipholipid syndrome (APS). (2007)
  • Author(s): Fujishima, N., Komatsuda, A., Ohyagi, H., Fupshima, M., Tada, M., Ohtani, H., Wakui, H., Hirokawa, M., Sawada, K.
  • Journal Title: Intern Med 45 Pages: 963-966
  • Peer Reviewed
• [Journal Article] Focal segmental glomerulosclerosis associated with polycythemia vera: report of a case and review of the literature. (2007)
  • Author(s): Okuyama, S., Hamai, K., Fujishima, M., Ohtani, H., Komatsuda, A., Sawada, K., Wakui, H.
  • Journal Title: Clin Nephrol 68 Pages: 412-415
  • Peer Reviewed
• [Journal Article] Interaction of alpha-actinin-4 with class I PxxP motif-containing OK/SW-CL. 16 protein. (2007)
  • Author(s): Togashi, M., Okuyama, S., Wakui, H., Komatsuda, A., Suzuki, D., Toyoda, M., Sawada, K.
  • Journal Title: Nephron Exp Nephrol 107
  • Peer Reviewed
• [Journal Article] Retrospective nationwide survey of Japanese patients with transfusion-dependent MDS and aplastic anemia highlights the negative impact of iron overload on morbidity/mortality. (2007)
  • Author(s): Takatoku, M., Uchiyama, T., Okamoto, S., Kanakura, Y., Sawada, K., Tomonaga, M., Nakao, S., Nakahata, T., Harada, M., Murata, T., Ozawa, K., on behalf of the Japanese National Research Group on Idiopathic Bone Marrow Failure Syndromes.
  • Journal Title: Eur J Hematol 78 Pages: 487-494
  • Peer Reviewed
• [Journal Article] Bone marrow-derived cells mobilized by granulocyte-colony stimulating factor facilitate vascular regeneration in mouse kidney after ischemia/reperfusion Injury. (2007)
  • Author(s): Akihama, S., Sato, K., Satoh, S., Tsuchiya, N., Kato, T., Komatsuda, A., Hirokawa, M., Sawada, K., Nanjo, H., Habuchi, T.
  • Journal Title: Tohoku J Exp Med 213 Pages: 341-349
  • NAID: 10020277513
  • Peer Reviewed
• [Journal Article] Phagocytosis of co-developing megakaryocytic progenitors by dendritic cells in culture with thrombopoietin and tumor necrosis factor-α and its possible role in hemophagocytic syndrome. (2006)
  • Author(s): Saito Y, Hirokawa M, Saito K, Yong-Mei Guo, Hebiguchi M, Kawabarta Y, Komatsuda A, Takahashi N, Yamashita J, Sawada K
  • Journal Title: Blood 107(4) Pages: 1366-1374
• [Journal Article] Oligoclonal T cell expansion in blood but not in the thymus from a patient with thymoma-associated pure red cell aplasia. (2006)
  • Author(s): Fujishima N, Hirokawa M, Fujishima M, Wada C, Toyoshima I, Watanabe S, Sawada K
  • Journal Title: Haematologica 91(12 Suppl)
• [Journal Article] Regulation of protein 4.1R interactions with membrane proteins by Ca2+ and calmodulin. (2006)
  • Author(s): Nunomura W, Takakuwa Y
  • Journal Title: Front Biosci 11(5) Pages: 1522-1539
• [Journal Article] 再生不良性貧血・赤芽球癆の診断と治療 (2006)
  • Author(s): 澤田賢一
  • Journal Title: 臨床血液 47(3) Pages: 176-189
  • NAID: 10017550479
• [Journal Article] 赤芽球癆診療の参照ガイド-PRCAの診療基準と診療の参照ガイド作成のためのワーキンググループ- (2006)
  • Author(s): 澤田賢一, 浦部晶夫, 中尾眞二, 別所正美, 唐沢正光, 石田陽治, 小松則夫, 増田道彦, 廣川誠, 茂木睦仁, 小峰光博
  • Journal Title: 臨床血液 47(4) Pages: 316-330
• [Journal Article] 赤芽球癆の病態と治療 (2006)
  • Author(s): 澤田賢一
  • Journal Title: 臨床血液 47(11) Pages: 1438-1445
  • NAID: 10020298836
• [Journal Article] Transgenic over-expression of GATA-1 mutant lacking N-finger domain causes hemolytic syndrome in mouse erythroid cells. (2005)
  • Author(s): Nakano M, Ohneda K, Yamamoto-Mukai H, Slumizu R, Ohneda O, Ohmura S, Suzuki M, Tsukamoto S, Yanagawa T, Yoshida H, Takakuwa Y, Yamamoto M
  • Journal Title: Genes Cells 10(1) Pages: 47-62
• [Journal Article] Modulation of erythrocyte membrane mechanical function by protein 4.1 phosphorylation us from a patient with thymoma-associated pure red cell aplasia. (2005)
  • Author(s): Manno S, Takakuwa Y, Mohandas N
  • Journal Title: J Biol Chem 280(9) Pages: 7581-7587
• [Journal Article] Modulation of erythrocyte membrane mechanical function by protein 4.1 phosphorylation. (2005)
  • Author(s): Manno S, Takakuwa Y, Mohandas N.
  • Journal Title: J Biol Chem 280 Pages: 7581-7587
• [Journal Article] Bcr-abl induces autocrine IGF-1 signaling.
  • Author(s): Lakshmikuttyamma, A., Pastural, E., N Takahashi, N., Sawada, K., Sheridan, D.P., DeCoteau, J.F., Geyer, C.R.
  • Journal Title: Oncogene (掲載確定)
  • Peer Reviewed
• [Journal Article] Hypertrophic cranial pachymeningitis in a patient with Cogan's syndrome.
  • Author(s): Togashi, M., Komatsuda, A., Masai, R., Maki, N., Hatakeyama, T., Wakui, H., Sawada, K.
  • Journal Title: Clin Rheumatol (掲載確定)
  • Peer Reviewed
• [Journal Article] Phagocytosis of co-developing neutrophil progenitors by dendritic cells in a culture of human CD34+ cells with granulocyte-colony stimulating-factor and tumor necrosis factor-α.
  • Author(s): Saito, Y., Guo, Y-M., Hirokawa, M., Saito, K., Komatsuda, A., Takahashi, N., Fujishima, M., Fujishima, N., Yamashita, J., Sawada, K.
  • Journal Title: Int J Hematol (掲載確定)
  • NAID: 10025159159
  • Peer Reviewed
• [Journal Article] Acquired pure red cell aplasia: updated review of treatment.
  • Author(s): Sawada, K., Hirokawa, M., Fujishima, N.
  • Journal Title: Br J Haematol (掲載確定)
  • Peer Reviewed
• [Journal Article] Up-regulated expression of Toll-like receptors mRNAs in peripheral blood mononuclearcells from patients with systemic lupus erythematosus.
  • Author(s): Komatsuda, A., Wakui, H., Iwamoto, K., Ozawa, M., Togashi, M., Masai, R., Maki, N., Hatakeyama, T., Sawada, K.
  • Journal Title: Clin Exp Immunol (掲載確定)
  • Peer Reviewed
• [Journal Article] Reversible infliximab-related lymphoproliferative disorder associated with Epstein-Barr virus in a patient with rheumatoid arthritis.
  • Author(s): Komatsuda, A., Wakui, H., Nimura, T., Sawada, K.
  • Journal Title: Mod Rheumatol (掲載確定)
  • NAID: 10024151093
  • Peer Reviewed
• [Journal Article] Predominant tubulointerstitial nephritis in a patient with systemic lupus erythematosus: phenotype of infiltrating cells.
  • Author(s): Omokawa, A., Wakui, H., Okuyama, S., Togashi, M., Ohtani, H., Komatsuda, A., Ichinohasama, R., Sawada, K.
  • Journal Title: Clin Nephrol (掲載確定)
  • Peer Reviewed
• [Journal Article] Renal amyloidosis associated with extracapillary glomerulonephritis and vasculitis in a patient with inflammatory bowel disease treated with infiximab.
  • Author(s): Hatakeyama, T., Komatsuda, A., Matsuda, M., Togashi, M., Maki, N., Masai, R., Sawada, K., Wakui, H.
  • Journal Title: Clin Nephrol (掲載確定)
  • Peer Reviewed
• [Journal Article] Successful treatment of post-MRSA infection glomerulonephritis with steroid therapy.
  • Author(s): Okuyama, S., Wakui, H., Maki, N., Kuroki, J., Nishinari, T., Asakura, K., Komatsuda, A., Sawada, K.
  • Journal Title: Clin Nephrol (掲載確定)
  • Peer Reviewed
• [Book] 炎症性貧血 (2006)
  • Author(s): 澤田賢一
  • Publisher: 日本血液学会/臨床血液学会合同総会、Educational Program Book
• [Book] Acquired aplastic anemia and pure red cell aplasia. (2005)
  • Author(s): Sawada K
  • Publisher: In Education Program Book, 30-37, Ann Meeting, JSH/JSCH
• [Book] 幹細胞・造血因子:高齢者の血液疾患(森真由美 編集) (2005)
  • Author(s): 澤田賢一
  • Publisher: 医薬ジャーナル社