GPI ANCHORED PROTEIN DEFICIENCIES IN CELLS FROM PSORIATIC SKIN

银屑病皮肤细胞中 GPI 锚定蛋白缺陷

• 批准号: 6235778
• 负责人: Mark Lehrman
• 金额: $ 5.04万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-06-10 至 1998-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6235778
• 关键词: CD antigens; biopsy; fibroblasts; gene expression; glycolipids; glycosylphosphatidylinositols; human tissue; keratinocyte; lipid biosynthesis; lipid metabolism; membrane lipids; peptides; phosphatidylinositols; polysaccharides; protein biosynthesis; protein degradation; protein metabolism; psoriasis; tissue /cell culture

Abroad spectrum of eukaryotic proteins are attached to cell surfaces by glycosylphosphatidylinositol (GPI) anchors. Such proteins include neuronal cell adhesion molecule, decay accelerating factor, scrapie prion protein, folate receptor, Thy-1 antigen, and the trypanosoma variant surface glycoprotein. The central features of GPI anchors are: (I) a residue of phosphatidylinositol, which is embedded in the plasma membrane; and (ii) a linear glycan stalk (1 glucosamine residue followed by 3 mannose residues, with a residue of ethanolamine-P linked to the 3rd mannose) with a glycosidic linkage attaching the glucosamine residue to the inositol residue of the phosphatidylinositol. The carboxy-terminal ends of protein molecules are attached to preassembled GPI anchors through the amine group of the ethanolamine-P. Psoriasis is a skin disease which affects many individuals, but its cause is unknown. Recently, histochemical analyses have suggested that GPI anchored proteins are highly deficient in psoriatic skin. This could be caused by (a) defective synthesis of preassembled anchors; (b) failure to attach anchors to proteins; ~ enzymatic cleavage of the anchors by phospholipases; and/or (d) proteolytic degradation of GPI anchored proteins. Methods for studying all of these possibilities have been described in the literature in detail, and are available in the P.I.~s laboratory. Experiments in this proposal will determine directly whether biosynthesis or catabolism of GPI anchored proteins is defective in cells derived from patients with psoriasis skin. The approach is to apply proven methods for GPI-anchor analysis to primary cultures of psoriatic fibroblasts and keratinocytes. In addition, a novel approach based upon recent research in the P.I.~s laboratory involving the use of synthetic GPI analogues will also be used to address this question.

真核蛋白的国外谱系附着在细胞上 糖基磷脂酰肌醇（GPI）锚的表面。 这样的 蛋白质包括神经元细胞粘附分子，衰减 加速因子，crapie prion蛋白，叶酸受体，THY-1 抗原和锥虫变异表面糖蛋白。 这 GPI锚的主要特征是：（i） 磷脂酰肌醇，嵌入质膜中； （ii）线性聚糖茎（1个葡萄糖胺残基，然后是3 甘露糖残留物，乙醇胺-P残留与 第三甘露糖）带有糖苷连接葡萄糖的糖苷连接 残留到磷脂酰肌醇的肌醇残基。 这 蛋白质分子的羧基末端连接到 预组装GPI锚定在 乙醇胺-P。 牛皮癣是一种皮肤病，会影响许多 个人，但其原因尚不清楚。最近，组织化学 分析表明，GPI锚定蛋白很高 牛皮癣的皮肤不足。这可能是由于（a）缺陷引起的 合成预组装的锚； （b）未将锚点附加到 蛋白质； 〜通过磷脂酶对锚定的酶促切割； 和/或（d）GPI锚定蛋白的蛋白水解降解。 研究了所有这些可能性的方法 在文献中详细说明，可在P.I. 实验室。 该提案中的实验将直接决定 GPI锚定蛋白的生物合成还是分解代谢是 来自牛皮癣皮肤患者的细胞中有缺陷。 这 方法是将经过验证的GPI锚分析方法应用于 银屑病成纤维细胞和角质形成细胞的原发性培养物。 在 此外，一种基于P.I. 〜S的最新研究的新方法 涉及使用合成GPI类似物的实验室也将 用于解决这个问题。