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Development of new drug for intractable hyperlipidemia and its clinical application

Research Project

Project/Area Number 07557073
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section試験
Research Field 内分泌・代謝学
Research InstitutionKYOTO UNIVERSITY

Principal Investigator

KITA Toru  Kyoto University, Graduate School of Medicine, Professor, 医学研究科, 教授 (60161460)

Co-Investigator(Kenkyū-buntansha) ISHII Kenji  Kyoto University, Graduate School of Medicine, Instructor, 医学研究科, 助手 (00212811)
WAKATSUKI Yoshio  Kyoto University, Graduate School of Medicine, Lecturer, 医学研究科, 講師 (40220826)
KUME Noriaki  Kyoto University, Graduate School of Medicine, Instructor, 医学研究科, 助手 (20252455)
YOKODE Masayuki  Kyoto University, Graduate School of Medicine, Lecturer, 医学研究科, 講師 (20252447)
DOI Toshio  Kyoto University, Graduate School of Medicine, Lecturer, 医学研究科, 講師 (60183498)
Project Period (FY) 1995 – 1996
Project Status Completed (Fiscal Year 1996)
Budget Amount *help
¥15,000,000 (Direct Cost: ¥15,000,000)
Fiscal Year 1996: ¥5,000,000 (Direct Cost: ¥5,000,000)
Fiscal Year 1995: ¥10,000,000 (Direct Cost: ¥10,000,000)
KeywordsCholesterol / Apo B-protein / MTP / VLDL / CHO-cell / Hepatocytes / HSP-70 / Transgenic mouse / LDL / LDL受容体 / HMG-CoA還元酵素阻害剤 / 家族性複合型高脂血症 / 家族性高コレステロール血症 / WHHLウサギ
Research Abstract

We found apolipoprotein B-100 (apo B) secretion is regulated in response to the change of intracellular cholesteryl ester contents by adding low density lipoprotein (LDL). LDL caused a significant dose-dependent increase in apo B secretion, because of preventing the degradation of apo-B protein itself. Immediately after apo B protein is translated from mRNA of apo B,microsomal triglyceride transfer protein (MTP) makes assembly with apo B protein. As a result, VLDL particles are formed. Therefore MTP plays an important role for regulating VLDL production and secretion. To investigate this regulation, we first cloned full length of cDNA for MTP,succeeded to transfect MTP cDNA to CHO cells and detected MTP protein. We are now doing following experiments.
1) To establish MTP overexpression system in rabbit hepatocytes.
2) To establish transgenic mouse which over express MTP cDNA using transferin promoter.
3) To analyze proteins which could regulate post-translational modification of apo-B protein, suchi as MTP,HDP-70 and unknown protein.

Report

(3 results)
  • 1996 Annual Research Report   Final Research Report Summary
  • 1995 Annual Research Report
  • Research Products

    (68 results)

All Other

All Publications (68 results)

  • [Publications] Tanaka, M. et al.: "Regulation of apolipoprotein B secretion in hepatocytes from Watanabe heritable hyperlipidemic rabbit, an animal model of familial hypercholesterolemia." Aherosclerosis. 114. 73-82 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Ochi, H. et al.: "Elevated levels of cyclic AMP inhibits protein kinase-C independent mechanisms of endothelial PDGF-B chain and ICAN-1 gene induction by lysophosphatidylcholine" Circulation Research. 77. 530-535 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Kita, T. et al.: "Lessons concerning human lipoprotein metabolism from the study of the WHHL rabbit." Atherosclerosis. X. 111-113 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Uematsu, M. et al.: "Coexistent myelodysplastic syndrome and non-Hodgkin lymphoma. Report of a case and review of the literature." Int. J. Hematology. 62. 45-51 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Kume, N. et al.: "Involvement of protein kinase C-independent mechanisms in endothelial ICAM-1 up-regulation by lysophosphatidylcholine." Ann. N. Y. Acad. Sci.748. 541-542 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Komatsu, T. et al.: "Lipoprotein glomerulopathy with a new apolipoprotein E phenotype" Am. J. Kidney Diseases. 25. 952-953 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Nishida, R. et al.: "Endoscopic Sclerotherapy in a Rat Model of Esophageal Varices" Scand J. Gastroenterol. 30. 489-496 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Dekigai, H. et al.: "Mechanism of Helicobacter pylori-Associated Gastric Mucosal Injury" Digestive Diseases and Sciences. 40. 1332-1339 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Teramoot, T. et al.: "Clinical Efficacy of fluvastatin for hyperlipidemia in Japanese patients." Am. J. Cardiol.76. 33A-36A (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Yokode, M. et al.: "The macrophage and its role in atherogenesis" Internal Medicine. 34. 281-283 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Yokode, M. et al.: "cigarette smoke and lipoprotein modification : a possible interpretation for development of atherosclerosis." Ann. N. Y. Acad. Sci.748. 294-301 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Iehara, N. et al.: "Differentiation of smooth muscle phenotypes in mouse mesangial cells." Kid. Int.49. 1330-1341 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Iehara, N. et al.: "Advanced glycosylation endoproducts modulate transcriptional regulations of type IV collagen and α-smooth muscle actin on mesangial cells." Nephrology. 118. 141-146 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Uematsu-Yanagita, M. et al.: "Microscopic polyarteritis during polymyalgia rheumatica remission." Am. J. Kid. Dis.28. 289-291 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Yokode, M. et al.: "Modification of high-and low-density lipoproteins by cigarette smoke oxidants." The Ann. N. Y. Acad. Sci.786. 245-251 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Kita, T. et al.: "Lysophosphatidylcholine induced gene expression of endothelial platelet-derived growth factor-b-chain and intercellular adbesion molecule-1" Medical Science Symposia Series. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Kita, T. et al.: "Induction of endothelial platelet-derived growth factor-b-chain and intercellular adhesion molecule-1 by lysophosphatibylcholine" The Ann. N. Y. Acad. Sci.(in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Sakai, A. et al.: "P-selectin and vascular cell adhesion molecule-1 are focally expressed in aortas of hypercholesterolemic rabbits prior to intimal accumulation of Macrophages and T-lymphocytes." Arterioscler Thromb Vasc Biol.17. 310-316 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Nishi, E. et al.: "Lysophosphatidylcholine increases expression of heparin-binding epidermal growth factor-like growth factor in human T-lymphocytes." Circulation Research. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Sawamura, T. et al.: "Anovel endothelial receptor for oxidized LDL" Nature. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Tanaka, M., Otani, H., Yokode, M.& Kita, T.: "Regulation of apolipoprotein B secretion in hepatocytes from Watanabe heritable hyperlipidemic rabbit, an animal model of familial hypercholesterolemia." Atherosclerosis. 114. 73-82 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Ochi, H., Kume, N., Nishi, E.& Kita, T.Elevated: "levels of cyclic AMP inhibits protein kinase-C independent mechanisms of endothelial PDGF-B chain and ICAM-1 gene induction by lysophosphatidylcholine." Circulation Research. 77. 530-535 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Kita, T., Tanaka, M., Otani, H., Kume, N.& Yokode, M.: "Lessons concerning human lipoprotein metabolism from the study of the WHHL rabbit." Atherosclerosis. X. 111-113 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Uematsu, M., Ochi, H., Ueda, Y., Hakamata, Y., Yokode, M., Yoshida, Y.& Kita, T.: "Coexistent myelodysplastic syndrome and non-Hodgkin lymphoma. Report of a case and review of the literature." Int.J.Hematology. 62. 45-51 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Kume, N., Ochi, H., Nishi, E., Gimbrone, M.A.& Kita, T.: "Involvement of protein kinase C-independent mechanisms in endothelial ICAM-1 up-regulation by lysophosphatidylcholine." Ann.N.Y.Acad.Sci.748. 541-542 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Komatsu, T., Kanatsu, K., Ochi, H., Kita, T.& Doi, T.: "Lipoprotein glomerulopathy with a new apolipoprotein E phenotype." Am.J.Kidney Diseases. 25. 952-953 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Nishida, R., Inoue, Y., Takimoto, H., Hamashima, H.& Kita, T.: "Endoscopic Sclerotherapy in a Rat Model of Esophageal Varices." Scand J.Gastroenterol. 30. 489-496 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Dekigai, H., Murakami, M.& Kita, T.: "Mechanism of Helicobacter pylori-Associated Gastric Mucosal Injury." Digestive Diseases and Sciences. 40. 1332-1339 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Teramoto, T., Goto, Y., Kurokawa, K., Nakamura, H., Yoshida, S., Saito, Y., Nakaya, N., Itakura, H., Takaku, F., Yamada, N., Hata, Y., Kuzuya, F., Mabuchi, H., Kita, T., Tarui, S., Matsuzawa, Y., Yamamoto, A., Tsushima, M., Kajiyama, G., Arakawa, K.& Ishioka, T.: "Clinical Efficacy of fluvastatin for hyperlipidemia in Japanese patients." Am.J.Cardiol. 76. 33A-36A (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Yokode, M.& Kita, T.: "The macrophage and its role in atherogenesis." Internal Medicine. 34. 281-283 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Yokode, M.Nagano, Y., Arai, H., Ueyama, K., Ueda, Y.& Kita, T.: "Cigarette smoke and lipoprotein modification : a possible interpretation for development of atherosclerosis." Ann.N.Y.Acad.Sci.748. 294-301 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Iehara, N.Takeoka, H., Tsuji, H., Imabayashi, T., Foster, D.N., Strauch, A.R., Yamada, Y., Kita, T.& Doi, T.: "Differentiation of smooth muscle phenotypes in mouse mesangial cells." Kid, Int.49. 1330-1341 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Iehara, N., Takeoka, H., Yamada, Y., Kita, T.& Doi, T.: "Advanced glycosylation endoproducts modulate transcriptional regulations of type IV collagen and alpha- smooth muscle actin on mesangial cells." Nephrology. 118. 141-146 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Uematsu-Yanagita, M., Cho, M., Hakamata, Y., Tanaka, M., Ishii, K.Kume, N., Ochi, H., Wakatsuki, Y., Yokode, M., Murakami, M., Yoshioka, H., Doi, T.& Kita, T.: "Microscopic polyarteritis during polymyalgia rheumatica ramission." Am.J.Kid.Dis.28. 289-291 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Yokode, M., Ueyama, K., Nagano, Y., Arai, H., Ueda, Y.& Kita, T.: "Modification of high- and low-density lipoproteins by cigarette smoke oxidants." The Ann.N.Y.Acad.Sci.786. 245-251 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Kita, T., Kume, N., Ochi, H., Nishi, E., Nagano, Y.& Yokode, M.: "Lysophosphatidylcholine induced gene expression of endothelial platelet-derived growth factor-b-chain and intercellular adhesion molecule-1." Medical Science Symposia Series. (in press.).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Kita, T., Kume, N., Ochi, H., Nishi, E., Sakai, A., Ishii, K., Nagano, Y.& Yokode, M.: "Induction of endothelial platelet-derived growth factor-b-chain and intercellular adhesion molecule-1 by lysophosphatidylcholine." The Ann.N.Y.Acad.Sci.(in press.).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Sakai, A., Kume, N., Nishi, E., Tanoue, K., Miyasaka, M.& Kita, T.: "P-selectin and vascular cell adhesion molecule-1 are focally expressed in aortas of hypercholesterolemic rabbits prior to intimal accumulation of Macrophages and T-lymphocytes." Arteriosclerosis, Thrombosis, and Vascular Biology. 17. 310-316 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Nishi, E., Kume, N., Ochi, H., Moriwaki, H., Wakatsuki, Y., Higashiyama, S., Taniguchi, N.& Kita, T.: "Lysophosphatidylcholine increases expression of heparin-binding epidermal growth factor-like growth factor in human T-lymphocytes." Circulation Research. (in press.).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Sawamura, T., Kume, N., Aoyama, T., Moriwaki, H., Hoshikawa, H., Aiba, Y., Tanaka, T., Miwa, S., Katsura, Y., Kita, T.& Masaki, T.: "A novel endothelial receptor for oxidized LDL." Nature. (in press.).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Tanaka,M.et al.: "Regulation of apolipoprotein B secretion in hepatocytes from Watanabe heritable hyperlipidemic rabbit,ananimal model of familial hyprecholesterolemia." Athelosclerosis. 114. 73-82 (1995)

    • Related Report
      1996 Annual Research Report
  • [Publications] Ochi,H.et al.: "Elevated levels of cyclic AMP inhibits protxein kinase-C independent mechanisms of endothelial PDGF-B chian and TCAM-1 gene induction by lysophosphatidylcholine." Circulation Research. 77. 530-535 (1995)

    • Related Report
      1996 Annual Research Report
  • [Publications] Kita,T et al.: "Lessons concrening human lipoprotein metabolism from the study of the WHHL rabbit." Atherosclerosis. X. 111-113 (1995)

    • Related Report
      1996 Annual Research Report
  • [Publications] Uematsu,M.et al.: "Coexistent myelodysplastic syndrome and non-Hodgkin lymphoma.Report of a case and review of the literature." Int.J.Hematology. 62. 45-51 (1995)

    • Related Report
      1996 Annual Research Report
  • [Publications] Kume,N.et al.: "Involvement of protein kinase C-independent mechanisms in endothelial ICAM-1 up-regulation by lysophosphatidylcholine." Ann.N.Y.Acad.Sci.748. 541-542 (1995)

    • Related Report
      1996 Annual Research Report
  • [Publications] Komatsu,T.et al.: "Lipoprotein glomerulopathy with a new apolipoprotein E phenotype" Am.J.Kidney Diseases. 25. 952-953 (1995)

    • Related Report
      1996 Annual Research Report
  • [Publications] Nishida,R.et al.: "Endoscopic Sclerotherapy in a Rat Model of Esophageal Varices" Scand J.Gastroenterol. 30. 489-496 (1995)

    • Related Report
      1996 Annual Research Report
  • [Publications] Dekigai,H.et al.: "Mechanism of Helicobacterpylori-Associated Gastric Mucosal Injury" Digestive Diseases and Sciences. 40. 1332-1339 (1995)

    • Related Report
      1996 Annual Research Report
  • [Publications] Teramoto,T.et al.: "Clinical Efficacy of fluvastatin for hyperlipidemia in Japanese patients." Am.J.Cardiol.76. 33A-36A (1995)

    • Related Report
      1996 Annual Research Report
  • [Publications] Yokode,M.et al.: "The macrophage and its role in atherogenesis" Internal Medicine. 34. 281-283 (1995)

    • Related Report
      1996 Annual Research Report
  • [Publications] Yokode,M.et al.: "cigarette smoke and lipoprotein modification : a possible interpretation for development of a therosclerosis." Ann.N.Y.Acad.Sci.748. 294-301 (1995)

    • Related Report
      1996 Annual Research Report
  • [Publications] Iehara,N.et al.: "Differentiation of smooth musclephenotypes in mouse masangial cells." Kid.Int.49. 1330-1341 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Iehara,N.et al.: "Advanced glycosylation endoproducts modulate trascriptional regulations of type IV collagen and α-smooth muscle actin on mesangial cells." Nephrology. 118. 141-146 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Uematsu-Yanagita,M.et al.: "Microscopic polyarteritis buring polymyalgis rheumatica remission." Am.J.Kid.Dis.28. 289-291 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Yokode,M.et al.: "Modification of high-and low-density lipoproteins by cigarette smoke oxidants." The Ann.N.Y.Acad.Sci.786. 245-251 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Kita,T.et al.: "Lysophosphatidylcholine induced gene expression of endothelial platelet-derived growth factor-b-chain and intercellular adhesion molecule-1" Medical Science Symposia Series. (in press).

    • Related Report
      1996 Annual Research Report
  • [Publications] Kita,T.et al.: "Induction of endothelial platelrt-derived frowth gactor-b-chain and intercellular adhesion molecule-1 by lysophosphatidylcholine"

    • Related Report
      1996 Annual Research Report
  • [Publications] The Ann.N.Y.Acad.Sci.(in press).

    • Related Report
      1996 Annual Research Report
  • [Publications] Sakai,A.et al.: "P-selectin and vascular cell adhesion molecule-and focally expressed in aortas of hypercholesterolemic rabbits prior to intimal accumulation of Macrophages and T-lymphocytes." Arterioscler Thromb Vasc Biol.(in press).

    • Related Report
      1996 Annual Research Report
  • [Publications] Nishi,E.et al.: "Lysophosphatidylcholine increases expression of heparin-binding epidermal growth factor-like growth factor in human T-lymphocytes."

    • Related Report
      1996 Annual Research Report
  • [Publications] Circulation Research. (in press).

    • Related Report
      1996 Annual Research Report
  • [Publications] Sawamura,T.et al.: "A novel endothelial receptor for oxidized LDL" Nature. (in press).

    • Related Report
      1996 Annual Research Report
  • [Publications] Toru Kita, et al.: "Induction of endothelial platelet-derived growth factor-b-chain and intercellular adhesion molecule-1 by lysophosphatidylcholine." The Ann. N. Y. Acad. Sci.(in press).

    • Related Report
      1995 Annual Research Report
  • [Publications] Toru Kita, et al.: "Lysophosphatidylcholine induced gene expression of endothelial platelet-derived growth factor-b-chain and intecellular adhesion molecule-1." Medical Science Symposia Series. (in press).

    • Related Report
      1995 Annual Research Report
  • [Publications] Hiroshi Ochi, et al.: "Elevated levels of cyclic AMP inhibits protein kinase-C independent mechanisms of endothelial PDGF-B chain and ICAM-1 gene induction by lysophosphatidylcholine." Circulation Research. 77. 530-535 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Makoto Tanaka, et al.: "Regulation of apolipoprotein B secretion in hepatocytes from Watanabe heritable hyperlipidemic rabbit, an animal model of familial hypercholesterolemia." Atherosclerosis. 114. 73-82 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Noriaki Kume, et al.: "Involvement of protein kinase C-independent mechanisms in endothelial ICAM-1 up-regulation by lysophosphatidylcholine." Ann. N. Y. Acad. Sci.748. 541-542 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Toru Kita, et al.: "Lessons concerning human lipoprotein metabolism from the study of the WHHL rabbit." Atherosclerosis X. 111-113 (1995)

    • Related Report
      1995 Annual Research Report

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Published: 1995-04-01   Modified: 2016-04-21  

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