REGULATION OF ALPHA-L-FUCOSIDASE IN HEALTH AND DISEASE

α-L-岩藻糖苷酶在健康和疾病中的调节

• 批准号: 3230611
• 负责人: RICHARD A DI CIOCCIO
• 金额: $ 7.67万
• 依托单位: ROSWELL PARK CANCER INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-04-01 至 1994-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3230611
• 关键词: I cell disease; carbohydrate receptor; enzyme biosynthesis; enzyme linked immunosorbent assay; fucosidosis; gel electrophoresis; human tissue; immunocytochemistry; intracellular transport; lymphocyte; lysosomes; mannose; phosphorylation; posttranslational modifications; protein transport; radiotracer; scintillation spectrometry; tissue /cell culture

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.

从粗纤维中准确输送新合成的和水解酶 内质网驻留在溶酶体或细胞外液 涉及一系列的共翻译和翻译后修饰， 这些酶的蛋白质和碳水化合物部分。 磷酸甘露糖基 识别系统是新的指导机制 合成酸水解酶到溶酶体。 这个系统的本质是 通过酸性水解酶获得磷酸甘露糖残基，这导致 与特异性膜结合转运受体结合， 溶酶体 然而，有大量证据表明， 靶向酸性水解酶的途径，包括α-L-岩藻糖苷酶。 这 该提案将测试新制造的alpha-L-的交付这一假设 岩藻糖苷酶与淋巴样细胞中溶酶体的结合是由磷酸甘露糖基 依赖和独立的路径。 总体目标是确定 淋巴细胞中α-L-岩藻糖苷酶的分子途径要求 并确定运输缺陷的分子基础， 岩藻糖苷沉积和I-α-L-岩藻糖苷酶的淋巴细胞系 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）α-L-岩藻糖苷酶的类型和含量， 磷酸甘露糖受体，3）α-L- 岩藻糖苷酶，以及4）引起岩藻糖苷病的突变的确切性质， α-L-岩藻糖苷酶分泌异常。 这些调查应 （1）提供关于贩运甲型-L-半乳糖的要求的资料; 岩藻糖苷症和I细胞疾病，3）关于替代机制的信息 用于酸性水解酶的运输。 这些实验可以提供一个 合理治疗疾病的依据。