This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. MicroRNAs (miRNAs) are small noncoding RNAs that regulate protein production of target mRNAs through recognition and binding of partially complementary sites within 3'untranslated regions. The miRNA-183 family (miR-183fam) are a trio of evolutionary conserved neurosensory miRNAs whose coordinated spatiotemporal expression in the mouse inner ear suggests they are long term markers essential to sensory hair cell identity and function. A mouse model of miR-183fam misexpression has been generated which exhibits an age-related hearing loss phenotype. The hypothesis is that the timing and strength of miR-183fam abundance is critical to the normal development and homeostasis of mouse inner ear sensory hair cells and supporting cells through RNAi mediated regulation of downstream target genes. This proposal aims to: 1) complete histologic and physiologic assessments of FVB/N Tg(GFAP-183-96-182) homozygous mice to correlate its inner ear phenotype with miR-183fam misexpression in the organ of Corti and identify the earliest time and type of deficit which causes the age-related hearing loss;2) validate predicted miRNA-183fam regulation of notch receptor Jag1 and the downstream transcription factor Sox2 with heterologous luciferase reporter assays and through assessments of RNA and protein levels in affected transgenic tissues;3) identify primary biological pathways and candidate target genes changed by miR-183fam misexpression through organ of Corti Affymetrix microarray analysis. Direct effects on inner ear function through the modulation of specific miRNAs establishes a paradigm for novel miRNA mediated therapeutics to treat some form of human hearing loss. Elucidation of the mechanism Tg-miRNA mediated hair cell loss should yield modalities influencing organ of Corti homeostasis, which may be of therapeutic benefit to treat hearing loss disease. Completion these aims will serve as paradigm for elucidating miRNA function in general. Knowledge gained from this study will significantly influence the miRNA and hearing research communities by demonstrating miRNAs as crucial and potent factors in the development and homeostasis of the inner ear.
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