| Cerebral ischemia and primary brain tumor are leading neurologic diseases for which the prognosis is often poor. Currently, there is only one drug available for the acute treatment of stroke, and brain tumor patients suffer from one of the lowest mean survival times of any type of cancer. Therefore, new therapies for each disease would be welcome for millions of individuals and their families. In this dissertation I report novel findings that microRNAs play very specific roles after stroke, and that brain tumor cells can transfer microRNA from one cell to another. In stroke, I first report that miR-21 is upregulated in neurons of the ischemic boundary, and that this serves a protective role by reducing the number of apoptotic cells. Based on my in vitro studies, I propose that it does so by inhibiting translation of the death inducing ligand Fas ligand. Next, I show that in chronic ischemia the transcription factor serum response factor is activated and contributes to enhanced oligodendrogenesis. Furthermore, I provide evidence that this activation may be due to suppression of miR-9, miR-200b and miR-200c, which are algorithmically predicted to target serum response factor. Lastly, I show that brain tumor cells share microRNA in a gap junction dependant manner. This novel finding provides the first ever direct evidence that microRNAs can regulate translation beyond the cell in which they were transcribed and processed. Taken together, these data add a new layer of complexity to the growing field of microRNA dynamics in central nervous system pathologies. |
