REGULATION OF ALPHA-L-FUCOSIDASE IN HEALTH AND DISEASE

毛坯中新合成和水解酶的准确输送 内质网滞留在溶酶体或细胞外液中 涉及一系列共同的和翻译后的 这些酶的蛋白质和碳水化合物的部分。亚磷酸甘油酯 识别系统是指导新世纪发展的重要机制 合成酸性水解酶为溶酶体。这一制度的本质是 酸性水解酶获得磷酸芒果酚残基，从而导致 与特定的膜结合转运受体结合并递送到 溶酶体。然而，有相当多的证据表明， 靶向酸性水解酶的途径，包括α-L岩藻糖苷酶。这 提案将检验一种假设，即新制造的阿尔法-L- 磷酸甘露糖介导淋巴细胞岩藻糖苷酶对溶酶体的作用 依赖和独立的路径。总体目标是确定 淋巴细胞中α-L岩藻糖苷酶路由的分子要求 并确定运输过程中缺陷的分子基础 岩藻糖苷病淋巴细胞株中的α-L岩藻糖苷酶 细胞疾病患者。具体目标是研究1) α-L岩藻糖苷酶的磷酸化，2) 3)α-L受体的亚细胞定位。 岩藻糖苷酶，以及4)引起岩藻糖苷病的突变的确切性质和 α-L岩藻糖苷酶分泌异常。这些调查应该 提供1)关于贩运阿尔法-L的要求的信息-- 岩藻糖苷病和I细胞病，3)关于替代机制的信息 贩卖酸性水解酶。这些实验可以提供一种 合理的治病依据。

The accurate delivery of newly synthesized and hydrolases from the rough endoplasmic reticulum to residency in lysosomes or extracellular fluids involves a series of co- and post-translational modifications of the protein and carbohydrate moieties of these enzymes. The phosphomannosyl recognition system is an important mechanism for directing newly synthesized acid hydrolases to lysosomes. The essence of this system is the acquisition of phosphomannosyl residues by acid hydrolases, which leads to binding to specific membrane-bound transport receptors and delivery to lysosomes. However, there is considerable evidence suggesting alternate pathways for targeting acid hydrolases, including alpha-L-fucosidase. This proposal will test the hypothesis that the delivery of newly made alpha-L- fucosidase to lysosomes in lymphoid cells is mediated by phosphomannosyl dependent and independent pathways. The broad objectives are to determine molecular requirements for routing of alpha-L-fucosidase in lymphoid cells and to determine the molecular basis of the defects in the trafficking of alpha-L-fucosidase in lymphoid cell lines derived from fucosidosis and I- cell disease patients. Specific objectives are to research 1) the phosphorylation of alpha-L-fucosidase, 2) the type and content of phosphomannosyl receptors, 3) the subcellular localization of alpha-L- fucosidase, and 4) the precise nature of mutations causing fucosidosis and abnormal secretion of alpha-L-fucosidase. These investigations should provide 1) information concerning requirements for trafficking of alpha-L- fucosidosis and I-cell disease, 3) information about alternative mechanisms for trafficking of acid hydrolases. These experiments could provide a rational basis for treatment of disease.