GLYCOSIDASES AS RELATED TO SPHINGOLIPIDOSES

与鞘脂相关的糖苷酶

基本信息

批准号：
3393982
负责人：
YU-TEH LI
金额：
$ 15.63万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
1979
资助国家：
美国
起止时间：
1979-02-01 至 1991-01-31
项目状态：
已结题

项目摘要

Sphingolipidoses are a group of congenital disorders caused by the impaired catabolism of glycosphingolipids. Since the storage of partially degraded glycosphingolipids in the secondary lysosomes of various sphingolipidoses is linked to a deficiency of glycosidases, the enzyme deficiency was once considered to be the sole cause of the pathogenesis of sphingolipidoses. Through the past support of this grant, we have established that activator proteins are requisite for the enzymic hydrolysis of GM1 and GM2. We have also discovered a new variant of Type-AB GM2 gangliosidosis caused by a defect in Beta-hexosaminidase A. Our work, together with that of others, has resulted in the introduction of a new concept that both glycosidases and activator proteins are required for the catabolism of glycosphingolipids. Therefore, according to this new concept, sphingolipidoses can be caused by four different etiologies: a defect in either activator protein or glycosidases or a deficiency in either activator protein or glycosidase. In this grant period we would like to continue investigating the chemical pathology of sphingolipidoses by studying the catabolism of glycosphingolipids. Our specific aims are: a) to improve the isolation techniques for activator proteins which stimulate the hydrolysis of GM1 and Gm2 (GM1- and GM2-activators) and to further study their specificities and subcellular localization; b) to characterize activator proteins in human urine; c) to develop a sensitive method such as enzyme-linked adsorbent assay or radioimmunoassay for the detection of GM1- and GM2- activators and the clinical diagnosis of lipidosis due to the deficiency of activator protein; d) to complete the overall catabolic pathways of GM1 and GbOse4Cer; e) to study inhibitor proteins which inhibit the catabolism of glycosphingolipids, and f) to continue the isolation and characterization of glycosidases pertinent to sphingolipidoses. Our long term objective is to completely understand the role of activator proteins, inhibitor proteins, and their interaction with glycosidases and glycolipid substrates. This information will lead to the better understanding of the catabolism of glycosphingolipids and the molecular basis of sphingolipidoses.

鞘脂脂是由受损引起的一组先天性疾病糖脂果脂的分解代谢。由于存储部分退化各种鞘脂的二级溶酶体中的糖脂脂与糖苷酶的缺乏有关，酶缺乏症一次被认为是鞘脂发病机理的唯一原因。通过这笔赠款的过去支持，我们已经确定了激活者蛋白质是GM1和GM2的酶水解所必需的。我们有还发现 β-己糖胺酶A中的缺陷A。我们的工作以及其他工作，导致引入了两个糖苷酶的新概念激活蛋白是需要的糖磷脂。因此，根据这个新概念鞘脂可以由四种不同的病因引起：激活剂蛋白或糖苷酶或任何一种激活蛋白或糖苷酶。在这个赠款期间，我们想继续研究鞘脂的化学病理学研究糖磷脂脂的分解代谢。我们的具体目的是：a）改善激活蛋白的隔离技术的刺激蛋白 GM1和GM2（GM1-和GM2激活剂）的水解，并进一步研究他们的特殊性和亚细胞定位； b）表征人尿中的激活蛋白； c）开发一种敏感方法，例如酶联的吸附剂测定或放射免疫测定法检测GM1- GM2-激活剂以及由于激活蛋白的缺乏； d）完成整体分解代谢 GM1和Gbose4cer的途径； e）研究抑制抑制剂的抑制剂糖磷脂脂的分解代谢，以及f）继续隔离和与鞘脂有关的糖苷酶的表征。我们的漫长术语目标是完全了解激活蛋白的作用，抑制剂蛋白质及其与糖苷酶和糖脂的相互作用基材。这些信息将导致对糖磷脂的分解代谢和分子基础鞘脂。