RNA editing by ADARs of dsRNA inhibits activation of the innate immune response. We rescued the Adar mouse embryonic lethality in an Adar1; Mavs double mutants that prevent this antiviral response. These mice die soon after birth and we will test whether removing the dsRNA -activated Protein Kinase R completes the rescue.
ADAR2 RNA editing changes specific codons in neuronal transcripts. Human ADAR2 mutations cause infant epilepsy and we will use cell lines to investigate the molecular mechanisms involved when ADAR2 mutations slightly reduce editing. We will study changes in the glutamate receptors of Adar2 mutant mice that develop seizures and use a mouse seizure model to study changes in Adar2 as seizures progress.
Mutant Drosophila Adar brain defects are rescued by human ADAR2. There is also an innate immune induction in Adar mutant brains, paralleling the Adar1 mutant. We will examine Adar effects on behaviours through editing of specific CNS transcripts as well as the circadian rhythm which is aberrant. We plan bioinformatics projects across all ADAR RNA editing models.

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