情報伝達におけるスフィンゴリビドの役割

1997 Fiscal Year Final Research Report Summary

• Project/Area Number: 09044272
• Research Category: Grant-in-Aid for international Scientific Research
• Allocation Type: Single-year Grants
• Section: Joint Research
• Research Field: Functional biochemistry
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: 飯田 静夫 東京医科歯科大学, 医学部, 教授 (00009987)
• Co-Investigator(Kenkyū-buntansha): CHATTERJEE S The Johns Hopkins University, School of M, 教授 ; YU Robert K. Medical College of Virginia Virginia Com, 教授 ; LI YuーTeh Tulane University, School of Medicine, 教授 ; 笠間 健嗣 東京医科歯科大学, 医学部, 助教授 (80124668) ; 櫛 泰典 東京医科歯科大学, 医学部, 講師 (60177988)
• Project Period (FY): 1997
• Keywords: スフィンゴリビド / 情報伝達 / 糖脂質 / 糖転移酵素 / 抗糖脂質抗体 / 自己免疫性疾患 / 動脈硬化 / 癌転移

Research Abstract

スフィンゴリビドはスフィンゴミエリンサイクルなどを介した細胞内情報伝達系の他に細胞間シグナル、相互認識分子、レセプターの制御分子としても働くことがわかってきた。しかし関連する因子、経路ともに未だ不明の点が多い。この研究ではスフィンゴリビドの代謝機構、代謝産物とその局在性などの基礎的な研究を基盤に、1)スフィンゴリビド代謝、特に生合成系の糖転移酵素のクローニングと発現調節、分解酵素とそのアクチベータ-タンパク質。2)細胞間相互作用、特に癌細胞の接着に働くスフィンゴリビド。3)細胞の増殖・分化、アポトーシスに関与するスフィンゴリビド。4)スフィンゴリビドに対する抗体で発症する自己免疫性疾患、を中心に研究を進め以下の成果を得た。
糖転移酵素関連ではガングリオシドGT3合成に働くα2、8シアル酸転移酵素とヒトのガラクトセレプロシド合成に働くガラクトース転移酵素のcDNAクローニングを行った。糖脂質の分解についてはGM2アクチベータ-タンパク質の遺伝子構造、基質特異性を検討し、その作用機序を明らかにした。細胞増殖・分化との関連では動脈硬化でラクトシルセラミドが酸化LDLと一緒にMAPキナーゼの経路を介して血管平滑筋細胞の増殖を促進する事、グロボ系列の糖脂質が神経細胞の分化に果たす役割、神経細胞のスフィンゴリビドによるアポトーシスについて研究を進めた。癌細胞の標的臓器への転移に糖脂質が特異的接着の分子として働くことを明らかにした。自己免疫性神経疾患における抗糖脂質抗体の作用機序を解明した。
その他、新しい酵素活性や結合能の測定法、糖脂質と機能的に類似のペプチドをペプチドランダムファージライブラリーから探索する方法の開発を行った。

Research Products

• [Publications] Yu-Teh Li: "Interaction of GM2 activator protein with glycosphingolipids." Journal of Biological Chemistry. 272. 2828-2833 (1997)
• [Publications] Yu-Teh Li: "Structyral Organization and Expression of the Gene for the Mouse GM2 activator protein." Mamm.Genomes. 8. 90-93 (1997)
• [Publications] Yu-Teh Li: "alpha-KDOase activity in Oyster and Synthesis of α-and β-4-Methylumbelliferyl ketosides of 3-deoxy-D-manno-octulosonic acid." Journal of Biological Chemistry. 272. 26419-26424 (1997)
• [Publications] Yu-Teh Li: "Synthesis of 6'-GM2,a regioisomer of ganglioside GM2,for studying the mechanism of action of GM2 activator." Carbohydrate Research. 302(3-4). 233-227 (1997)
• [Publications] Yu-Teh Li: "GM2 Activator Protein" Trends in Glycoscience and Glycotechnology. 9. 421-432 (1997)
• [Publications] Yu-Teh Li: "Specificity of Mouse GM2 Activator Protein and b-N-Acetylhexosaminidase A and B.SIMILARRITIES AND DEFFERENCES WITH THER HUMAN COUNTERPARTS IN THE CATABOLISM OF GM2.." Journal of Biological Chemistry. 273. 66-72 (1998)
• [Publications] Robert K.Yu: "Antibodise to giycosphingolipid antigens in patients with immune-induced cochleovestibular disorders" Amer.J.Otology. 18. 175-178 (1997)
• [Publications] Robert K.Yu: "Cloning of cDNA coding for rat brain CMP-NeuAc:GD3 α 2-8 sialytransferase" Gene. 187. 131-134 (1997)
• [Publications] Robert K.Yu: "Glycosyltransferase activities in cultured endothelial cells of bovine brain microvascular origin." Neurochemical Research. 22. 463-466 (1997)
• [Publications] Robert K.Yu: "Unusual gangliosidosis in emu (Dromaius novaehollandiae)" Journal of Neurochemistry. 68(5). 2070-2078 (1997)
• [Publications] Robert K.Yu: "Cloning,characterization,and expression of human ceramide galactosyltransferase cDNA" Biochemical & Biophysical Research Communications. 232(2). 449-453 (1997)
• [Publications] Robert K.Yu: "The role of globo-serie glycolipids in neuronal cell defferentiation A review." Neurochemical Research. 23. 291-303 (1998)
• [Publications] Robert K.Yu: "Heritability and biochemistry of gangliosidosis in emus." Avian Diseases. 41. 838-849 (1997)
• [Publications] Robert K.Yu: "The role of sphingolipid-mediated cell death in neurodegenerative diseases." J.Lipid Res.39. 838-849 (1997)
• [Publications] Robert K.Yu: "On the specificity of anti-sulfoglucuronosyl glycolipid antibodies." J.Carbohydrate Chem. (in press).
• [Publications] Robert K.Yu: "Sulfogucuronosyl glycopids as putative antigens for autoimmune inner ear disease." J.Neuroimmunol. (in press).
• [Publications] Robert K.Yu: "The role of glycosphingolipids in neurological disorders:Mechanisms of immune action." Ann.New York Acad.Sci. (in press).
• [Publications] Robert K.Yu: "Isolation and functional analysis of the promoter of the rat CMP-NeuA GM3 α 2,8sialytransferase (GD3-synthase) gene." Journal of Biological Chemistry. (accpepted).
• [Publications] Subroto Chatterjee: "Oxidized low density lipoprot eins and lactosylceramide both stimulate the expression of proliferating cell nuclear antigen and the proliferation of aortic smooth muscle cells" Indian Jornal of Biochemistry & Biophysics. 34. 56-60 (1997)
• [Publications] Subroto Chatterjee: "A receptor-based immunoassay to detect Staphylococcus enterotoxin B in biological fluids." Analytical Biochemistry. 245. 213-217 (1997)
• [Publications] Subroto Chatterjee: "Oxidized low density lipoproteins stimulate galactosyltransferase activity,ras activation,p44 mitogen activated protein kinase and c-fos expression in aortic smooth muscle cells." Glycobiology. 7(5). 703-710 (1997)
• [Publications] Subroto Chatterjee: "Minimally modified low density lipoproteins induce aortic smooth muscle cell proliferation via the activation of mitogen activated protein kinase." Molecular & Cellular Biochemistry. 170(1-2). 85-89 (1997)
• [Publications] Subroto Chatterjee: "Redox-regulated signaling by lactosylceramide in the proliferation of human aortic smooth muscle cells." Journal of Biological Chemistry. 272(25). 15642-15649 (1997)
• [Publications] Subroto Chatterjee: "Acci,i;atopm pf glycosphingolipids in human atherosclerotic plaque and unaffected aorta tissues" Giyociology. 7(1). 57-65 (1997)
• [Publications] 田川 由美: "CIDPにおける抗SGP抗体" NEUROLOGICAL MEDICINE. 46(3). 272-278 (1997)
• [Publications] Takao Taki: "Canglioside GD1 α Functions in the Adhesion of Metastatic Tumor Cells to Endothelial Cells of the Target Tissue^1" CANCER RESEARCH. 57. 1882-1888 (1997)
• [Publications] Nobuhiro Yuki: "Pathogenesis of the neurotoxicity caused by anti-GD2 antibody therapy" Jornal of Neurological Sciences. 149. 127-130 (1997)
• [Publications] Takao Taki: "Preparation of pettides which mimic glycosphingolopids by using phage peptide library and their modulation on β-galactosidase activity" FEBS. 418. 219-223 (1997)
• [Publications] Nobuhiro Yuki: "Close association of Guillain-Barre syndrome with antibodies to minor Monosialogangliosides GM1b and GM1 α" Jornal of Neuroimmunology. 74. 30-34 (1997)
• [Publications] Kazuhiro Matsuda: "Structure of a novel phosphocholine-containing aminoglycerolipid of Mycoplasma fermentans" Biochimica et Biophysica Acta. 1349. 1-12 (1997)
• [Publications] Keiko Tadano-Aritomi: "Structural characterization of a novel mono-sulfated gangliotriaosylceramide containing a 3-O-sulfated N-acetylgalactosamine from rat kidney" Glycoconjugate Journal. 13. 285-293 (1996)
• [Publications] Kazuo Nakamura: "GANGLIOSIDES OF DOGGISH (SQUALUS ACANTHIAS) BRAIN" Neurochem.Int.30(6). 593-604 (1997)
• [Publications] Robert.K.Yu: "Molecular Biology of Multiple Sclerosis" Glycolipids of the CNS, 219-229 (1997)
• [Publications] Subroto Chattergee: "Oxygen Transport to Tissue XVIU" Plenum Press, 337-345 (1997)