A prominent theme in biology is the mechanism underlying the response of organisms to changes in their environment. miRNAs are small non-coding RNAs that serve as post-transcriptional regulators of gene expression. Translational control by miRNAs is emerging as a major regulatory component of many developmental, physiological and metabolic pathways. However, little is known about their role in behavior and more specifically in circadian rhythms. Circadian rhythms are endogenous and self sustained 24 hs rhythms that drive a plethora of physiologic and behavioral processes.
During my post doctoral training, I have demonstrated that miRNAs are involved in the generation and output pathways of the circadian clock. Moreover, I discovered that the master circadian gene, the transcription factor Clk is regulated by the miRNA bantam. To reach this conclusion I have developed new methodologies for the study of miRNAs and their mRNAs target in neuronal tissue. These include an experimental procedure to identify miRNA-regulated genes (RISC immuno-precipitation followed by microarray analysis) and a new approach to identify miRNAs expressed in a cell population without dissection and cell purification approaches (cell-specific inhibition of the miRNA biogenesis pathway followed by tiling array analysis).
The present proposal is focused on deepening my recent discoveries and on characterizing the mechanisms by which miRNA-mediated regulation controls the circadian clock at the biochemical and behavioral levels. For doing so, I plan to study: a) the components of the circadian machinery regulated by miRNAs; b) how this regulation is achieved; c) other behavioral processes that are also regulated by miRNAs. In particular I plan to dissect the mechanism by which Clk translation is regulated by miRNAs.
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