The primary objective of the proposal is to determine the roles of polysialic acid in development and tumor malignancy, and the roles of various a2,8-sialyltransferases in polysialic acid formation. The investigators have cloned a cDNA encoding polysialyltransferase, PST, that polysialylates the neural cell adhesion molecule, N-CAM. They found that PST alone can add all a2,8-linked sialic acid necessary for polysialic acid formation. By using this cDNA, they also demonstrated that polysialylated N-CAM facilitates neurite outgrowth and branching much better than N-CAM alone. Furthermore, they have found that polysialylated gangliosides can also be synthesized by a ganglioside-specific polysialyltransferase, GD3/GT3ST. Based on these findings, four major areas of further study are proposed as follows: 1. Elucidation of the roles fo various a2,8-sialyltransferases in polysialic acid formation. The studies will determine the roles of PST and other a2,8-sialyltransferases such as STX, ST8SiaIII and GD3/GT3ST in polysialic acid formation and their expression during embryonic development. 2. Determining the roles of polysialic acid in neural cell extension and tumor cell migration. 3. Determining the roles of polysialic acid in embryonic development. The studies will determine the roles of polysialic acid in mouse development by ectopic expression, and systemic and tissue-specific knock-out of PST gene. 4. Isolation of a novel carrier glycoprotein that contains polysialic acid. The studies will identify a novel glycoprotein(s) that carries polysialic acid and determine its expression in various tissues. These studies will allow the investigators to understand the physiological roles of polysialic acid during development and oncogenesis.
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