The spontaneity of cochlear sensory hair cell (HC) regeneration has been lost in mammalian species which is why human hearing loss is irreversible following HC death Several studies have established the potency of the transcription factor ATOH1 in dictating HC fate assignment, but recent work has shown that ATOH1 transdifferentiated HCs are physiologically and histologically immature. MicroRNAs (miRNAs) are small noncoding RNAs that regulate post-transcriptional activity of target mRNAs. The miRNA-183 cluster is a trio of evolutionary conserved neurosensory miRNAs whose coordinated spatiotemporal expression in the HCs suggests they are long term markers essential to HC identity and function. Transgenic FVB/N-Tg(GFAP-183- 96-182)1Mdw (Tg1Mdw) mice misexpress the miR-183 cluster in supporting cells (SCs) of the organ of Corti (OC) and show an increase in cochlear HCs; evidence that these miRNAs serve as positive effectors of SC to HC differentiation in the mammalian OC. Therefore, we believe increased rates of SC transdifferentiation and HC maturity will occur from simultaneous ATOH1 and miR-183 cluster expression. This proposal aims to: 1) compare the rates of HC transdifferentiation in PLP-CreERT+;Atoh1-HA+;Tg1Mdw and PLP-CreERT+;Atoh1-HA+; 2) compare the rates of HC transdifferentiation in PLP-CreERT+;Dicer-/- and PLP-CreERT+;Dicer+/-. Results generated from our studies should be beneficial to, and better inform, therapeutic efforts to renew damaged or diseased cochlear sensory epithelia. Completion of this study will have a positive impact on the auditory field and advance the biological relevance of miRNAs to regenerate lost HCs. Moreover, it will add novel and medically relevant mechanistic insights in post-transcriptional control of gene expression by miRNAs, which may lead to novel ways of thinking about how, when, and where to employ potential therapeutic RNAs to test their efficacy in the treatment of hearing loss disease.
Human hearing loss is irreversible following the death of sensory hair cells (HCs) in the cochlea. Our long- term goal is to discover the function(s) and therapeutic potential of evolutionally conserved miRNAs relevant to hearing research. The present application will allow us to generate direct evidence that miRNA post- transcriptional gene regulation promotes postnatal HC transdifferentiation. Results generated from our studies should be beneficial to, and better inform, therapeutic efforts to renew damaged or diseased cochlear sensory epithelia. Moreover, it will add novel and medically relevant mechanistic insights in post-transcriptional control of gene expression by miRNAs, which may lead to novel ways of thinking about how, when, and where to employ potential therapeutic RNAs to test their efficacy in the treatment of hearing loss disease.
