GLYCOLIPID PROTEIN ANCHORS IN PNH AND THY-1 MUTANTS

对磷脂酰肌醇敏感的含甘露糖的糖脂 (PI)在真核细胞中发现了特异性磷脂酶， 甘露糖脂（GPI-脂质）和作为所选膜的锚部分 GPI锚定蛋白（GPI anchored proteins） 最近的研究从这些和其他 实验室已经强烈表明，某些游离GPI脂质是 GPI锚的前体和中断其 GPI锚定蛋白的合成可能是GPI锚定蛋白缺乏表达的原因 对鼠Thy-1阴性T淋巴瘤突变体和循环红细胞的影响， 白色细胞溶血性贫血、阵发性睡眠性血红蛋白尿 （PNH）。 拟议的生物化学、细胞和分子生物学研究将 检查游离和蛋白质相关的结构和生物合成 GPI-脂质、GPI-脂质的囊泡转运和GPI-脂质的可能作用 GPI脂质是酶的底物，也是第二信使的来源。 在 为了进一步阐明GPI-脂质生物合成的途径， 特别关注现有的和新的人类和小鼠细胞突变体， 不表达GPI锚定蛋白，包括患有 Zellweger综合征，其特征是合成不足， 醚脂 相关研究将使用GPI的稳定再掺入- 锚定蛋白进入野生型细胞的质膜， 一种“细胞疗法”，将GPI脂质添加到突变细胞的表面 为了恢复它们表达GPI锚定蛋白的能力， 克隆导致GPI-脂质合成损伤的基因， 是导致这些蛋白质在细胞表面表达缺乏的原因。 PNH。

Mannose-containing glycolipids which are sensitive to phosphatidyl-inositol (PI) specific phospholipases are found in eukaryotic cells both as free mannolipids (GPI-lipids) and as anchor moieties of selected membrane proteins (GPI-anchored proteins). Recent research from these and other laboratories has strongly indicated that certain of the free GPI-lipids are precursors of the GPI anchors and that lesions which interrupt their synthesis may account for the lack of expression of GPI-anchored proteins on murine Thy-1 negative T lymphoma mutants and on circulating red and white cells in the hemolytic anemia, Paroxysmal Nocturnal Hemoglobinuria (PNH). The proposed biochemical, cell and molecular biological studies will examine the structures and biosynthesis of both free and protein-associated GPI-lipids, vesicular transport of GPI-lipids and the possible role(s) of GPI-lipids an enzyme substrates and as sources of second messengers. In order to further elucidate the path of GPI-lipid biosynthesis, studies will focus especially on available and new human and murine cell mutants which do not express GPI-anchored proteins, including cells of patients suffering from Zellweger syndrome, which is characterized by deficient synthesis of ether lipids. Related studies will use stable reincorporation of GPI- anchored proteins into the plasma membrane of wild type cells to initiate a line of "cell therapy", add GPI-lipids onto the surface of mutant cells in an attempt to restore their ability to express GPI-anchored proteins, and clone genes which account for the lesions in GPI-lipid synthesis which are responsible for the lack of cell surface expression of such proteins in PNH.