Biology of mammalian Sialidases

唾液酸酶存在于病毒、细菌、真菌、鸟类和哺乳动物中。哺乳动物唾液酸酶在其特异性、最适pH、亚细胞定位和组织表达方面存在差异。到目前为止，已经克隆了四个唾液酸酶基因(NEU1-4)。我这个项目的总体目标是研究唾液酸化在生物系统中的细胞作用。确定唾液酸酶对复杂的生理和细胞过程的功能影响应该揭示唾液酸酶敏感的唾液酸对糖蛋白和糖脂的生物学意义。该方案的短期目标是：(1)体外鉴定小鼠neu4启动子及其顺式作用元件。(2)探讨NEU4唾液酸酶对肌肉分化的影响。(3)研究NEU4在细胞内的定位和转运。(4)研究NEU4对潜在靶分子唾液酸化的功能影响。NEU4表达的调节可能不仅对唾液酸糖共轭的分解至关重要，而且在肌肉分化过程中重要功能事件的激活或失活中也是必不可少的。建议的研究应该确定调控NEU4表达、功能和运输的分子机制。唾液酸酶基因家族的转录调控及其功能作用将决定许多唾液酸化靶标的翻转或修饰对一系列生物学功能的影响。

Sialidases are found in viruses, bacteria, fungi, avians and mammals. Mammalian sialidases differ in their specificity, pH optimum, subcellular localization and tissue expression. To date, four genes encoding sialidases (neu1-4) have been cloned. The overall objective of my program is to investigate the cellular role of sialylation in biological systems. Defining the functional impact of sialidases on complex physiological and cellular processes should uncover the biological significance of sialidase-susceptible sialic acids on glycoproteins and glycolipids. The short term objective of this proposal is: (1) To characterize the mouse neu4 promoter and their functional cisacting elements in vitro. (2) To investigate the impact of NEU4 sialidase on muscle differentiation. (3) To investigate the intracellular localization and trafficking of NEU4. (4) To characterize the functional impact of NEU4 on sialylation of potential target molecules. Modulation of NEU4 expression may be essential not only for the breakdown of sialylated glycoconjugates but also in the activation or inactivation of functionally important events during muscle differentiation. The proposed studies should define the molecular mechanisms that regulate NEU4 expression, function and transport. Transcriptional control of the sialidase gene family and their functional roles will define the impact of the turnover or modification of many sialylated targets on a vast array of biological functions.