Hereditary inner ear disease is prevalent and has significant implications for quality of life. There is currently no available clinical cure for hereditary inner ear disease. The mouse serves as an ideal mammalian model for understanding genetic inner ear disease and for developing therapeutic measures. Mouse models have facilitated the discovery of genes that underlie hereditary disease in humans, have made it possible to study the role of these genes in inner ear development and function, and hold great promise as models for developing treatments for hereditary inner ear disease. This grant application builds on our discovery that mutations in the unconventional myosin gene, Myo15, are responsible for profound congenital deafness in humans with DFNB3 and in two spontaneous mouse mutants with profound recessive deafness, shaker 2 and shaker 2J. We propose to use these two mouse models of DFNB3 to establish the structure and functional properties of this large myosin, the requirement for expression in utero and early postnatal life, and the developmental basis for pathology in affected individuals. As each of these goals are accomplished we will move closer toward the ultimate objective of gene therapy for congenital deafness in children and expand our molecular understanding of the basic hearing process. In the first aim, we will rigorously test the long-term functional and structural outcome of the phenotypic correction of deafness in shaker 2 mice that we accomplished by complementation with a BAC transgene.
The second aim tests the hypothesis that MYOSIN XV-deficient hair cells fail to detach from the basement membrane during development, leading to cellular pathology.
The third aim examines whether loss of Myo15 function is partially compensated by the function of other myosins.
The fourth aim tests whether the unusual N-terminal third of the MYOXV protein is important for function using transgenic mice. Finally the feasibility of gene therapy for DFNB3 in newborns or young children will be assessed in the last aim using inducible expression of Myo15 transgenes in young, postnatal shaker 2 mice. Our investigative team has a track record for accomplishments resulting from cross disciplinary collaboration, which has brought expertise in otolaryngology and morphology together with expertise in molecular and developmental genetics. Our interdisciplinary approach is essential to fully exploit the animal models that will be the basis for developing and testing therapy for hereditary inner ear disease.
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