The Tectorial Membrane and the Sensory Hair Bundles of the Inner Ear: Mechanisms of Development and Effects of Deafness-Related Mutations.

The aim is to understand the development, maturation and dysfunction of two key components of the cochlea, the tectorial membrane and the sensory hair bundle. Analysis of mice with mutations affecting the structure and attachment of the tectorial membrane, and misexpression of tectorial-membrane proteins, will reveal the molecular mechanisms underlying the normal development of this matrix and how its constituent elements are organised. Mouse models will be used to analyse why mutations in the g ene encoding Tecta cause progressive forms of hereditary deafness and if mutated Tecta protein exacerbates the detrimental effects of loud sounds. Ectopic expression of the hair-bundle link protein stereocilin will be used to determine if it can mediate tectorial-membrane attachment. Targeted inactivation of the enzymatic and G-protein-mediated activities of two orphan receptors of the hair bundle (Ptprq and Vlgr1) will assess structural roles for these proteins, and imaging techniques will dete rmine if they can be force-activated. A mouse model for a novel human mutation causing aminoglycoside-induced hearing loss will be created to study how the mutant hair-bundle protein enhances sensitivity to aminoglycosides. These studies will determine how the tectorial membrane and the hair bundle develop, and reveal how environmental factors interact with mutations in inner-ear proteins.