Intracellular RNA trafficking provides a mechanism to target gene expression to particular sub-cellular regions and to minimize ectopic expression elsewhere in the cell. Previous work has shown that eucaryotic RNAs are assembled into trafficking intermediates termed """"""""granules."""""""" The direction and velocity of RNA granule trafficking is determined by cis-acting sequences in the RNA, trans-acting factors that bind to the RNA, and molecular motors (kinesin and dynein) that move RNA granules along microtubules. The central hypothesis of this proposal is that RNA trafficking is controlled by the balance of power between the opposing molecular motors kinesin and dynein in each granule. We will investigate 1) the mechanism of RNA granule assembly, 2) the movement of RNA granules along microtubules, 3) the regulation of kinesin and dynein activities by cis/trans trafficking determinants and 4) the steering of RNA trafficking in oligodendrocytes. The results will have significance for understanding the pathogenesis of demyelinating diseases such as multiple sclerosis that affect oligodendrocytes, the cellular and molecular mechanisms of learning and memory and synaptic plasticity in neurons, the control mechanisms for viral replication in HIV infected cells, and the molecular basis for some of the 82 different human diseases that involve intracellular trafficking.
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