DRUG INTERACTIONS WITH BRAIN MICROTUBULE PROTEINS

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Microtubules are widely distributed in eucaryotic cells and tissues, and are especially abundant in the central nervous system. They are essential to a large number of cellular processes, particularly those concerned with the development and maintenance of cell shape, changes in cell shape, and certain forms of cell motility. It is evident that microtubules must play vital roles in CNS function. For example, they appear to be essential to the development and maintenance of the asymmetric shape characteristic of neuronal cells; and it seems likely that they are involved in both slow and fast axoplasmic transport. However, there is as yet no biochemically defined knowledge as to what the true mechanistic functions of microtubules are, and the specific role(s) of microtubules in the CNS remain largely unknown. The main objectives of this research are to characterize brain microtubule (neurotubule) biochemistry and function with the use of two experimental approaches. One approach focuses on investigation of the biochemical properties of tubulin and other microtubule-associated proteins from the chick and bovine CNS. Some of the specific questions will be concerned with characterization of the subpopulations of microtubules in the CNS, and with regulation of opposite-end assembly and disassembly of brain microtubules. The second approach involves investigation of the biochemical mechanisms of action of drugs that inhibit microtubule polymerization. Studies on the interactions of drugs with tubulin not only yield information on the biochemical mechanisms of action of the drugs, but also provide valuable information on the biochemical properties and functional roles of microtubles. The purpose of these studies is to define the biochemical properties of microtubule protein which are related to microtubule functions, with the long-term goal of understanding the roles of microtubules in relation to brain function.