MOLECULAR STUDIES ON THE MANNOSE 6-PHOSPHATE RECEPTOR

溶酶体是降解正常细胞的主要场所， 选民。 超过30种可遗传的"储藏疾病"是由 溶酶体水解酶活性的特定缺陷。 溶酶体缺陷 功能也是衰老和各种营养的特点 紊乱 获得性疾病中的溶酶体损伤导致 细胞外释放活化的水解酶，通常产生坏死 和细胞死亡。 甘露糖6-磷酸受体负责定位许多 溶酶体中的水解酶。 它结合水解酶后，立即 合成并促进它们包装到溶酶体中。 受体 也在细胞表面起作用以促进酸性水解酶的去除 从细胞外位点。 长期目标是确定甘露糖的分子基础 6-磷酸盐受体功能 重组DNA技术将用于 在受体中引入结构变化，将使用生物学方法 以检测它们对受体功能的特定方面的影响。 的 该建议的直接目标，即克隆编码 甘露糖6-磷酸受体并确定受体的结构， 为实现这一目标奠定了基础。 这些研究将有助于 对我们理解溶酶体生物发生，细胞内膜 运输和蛋白质分选。

Lysosomes are the primary site for degradation of normal cellular constituents. Over 30 inheritable "storage diseases" are caused by specific defects in lysosomal hydrolase activities. Defective lysosomal function is also characteristic of aging and various nutritional disorders. Lysosomal injury during acquired diseases results in extracellular release of activated hydrolase which often produces necrosis and cell death. The mannose 6-phosphate receptor is responsible for localization of many hydrolases in lysosomes. It binds the hydrolases immediately after their synthesis and facilitates their packaging into lysosomes. The receptor also functions on the cell surface to facilitate removal of acid hydrolases from extracellular sites. The long range goal is to determine the molecular basis of mannose 6-phosphate receptor function. Recombinant DNA techniques will be used to introduce structural changes in the receptor, biologic methods will be used to examine their effects on specific aspects of receptor function. The immediate objectives of this proposal, namely to clone a cDNA encoding the mannose 6-phosphate receptor and determine the structure of the receptor, provide the basis for achieving this goal. These studies will contribute to our understanding of lysosome biogenesis, intracellular membrane trafficking and protein sorting.