MicroRNAs are small noncoding RNAs that regulate protein production of target mRNAs through recognition and binding of partially complementary sites located within the 3' untranslated region. The long-term goals of this research are: 1) identify miRNAs critical to inner ear development and homeostasis; 2) establish the degree to which miRNAs dictate inner ear cell fate establishment and homeostasis; 3) identify miRNA directed cellular pathways that intersect hearing disease etiology and implicate signaling pathways and/or novel avenues for potential theraputic intervention. Preliminary data are presented that show the expression of a trio of miRNAs that are significantly and specifically increased concomitant with mouse inner ear maturation. The hypothesis is that the upregulation of miRs 96, 182 and 183 is required for normal maturation and/or homeostasis through its contribution to downstream target gene regulation. Independent miRNA target gene prediction algorthims identify several potential target mRNAs known to be active participants in inner ear biology, including several transcription factors, signaling ligands and receptors.
The specific aims of this revised application are: 1) establish the embryonic pattern of miR 96, 182, and 183 expression in the mouse ear; 2) Determine if miRs 96, 182 and 183 inhibit expression of predicted target genes and affect the expression of hair cells marker genes using cell lines from early embryonic mouse inner ear and 3) begin to generate a novel transgenic mouse where endogenous levels of these miRNAs are missexpressed in either the entire ear or supporting cells to study the effects of miR 96,182 and 183 dysregulation in vivo. Fulfillment of the stated objectives will provide novel reagents and a proof of principle that modulation of specific miRNA expression leads to direct effects on inner ear function, thus establishing a paradigm for novel miRNA mediated therapeutics. ? ? ?
| Weston, Michael D; Pierce, Marsha L; Jensen-Smith, Heather C et al. (2011) MicroRNA-183 family expression in hair cell development and requirement of microRNAs for hair cell maintenance and survival. Dev Dyn 240:808-19 |
| Okoruwa, Oseremen E; Weston, Michael D; Sanjeevi, Divvya C et al. (2008) Evolutionary insights into the unique electromotility motor of mammalian outer hair cells. Evol Dev 10:300-15 |
