Our sense of gravity and linear acceleration is critical for spatial orientation and balance. Such sense is mediated by stimulation of vestibular hair cells by the displacement of otoconia against the sensory epithelium in the inner ear. Otoconia-related balance disorders and dizziness are a significant health issue that affects over 6 million adults in the United States. This problem is worse in the elderly. Despite the identification of a number of proteins involved in otoconia/otolith abnormalities, neither the functions of the proteins nor the mechanisms or processes of crystal formation are defined. Using a gene targeting strategy, we have demonstrated that the predominant mammalian otoconial protein, otoconin-90/95 (as Oc90), is an essential organizer of the organic matrix of otoconia by recruiting other components important for calcification. Oc90 null mice have giant """"""""otoconia"""""""" with a greatly reduced number, which leads to balance deficits. This proposal is designed to perform in- depth quantitative expression studies and protein biochemical analyses to address the roles of Oc90 and otolin in providing optimal otoconia calcification and to identify factors critical for the spatial specific development of otoconia. We will rigorously test the hypothesis that Oc90 specifically recruits an important otoconin, otolin, for otoconia matrix formation and seeding and identify the mechanism underlying such specificity. We will then use the existing o>tectorin null mice to generate double knockouts of Oc90/a-tectorin to test the hypothesis that these two proteins facilitate each other in otoconia seeding due to their mutual interactions with otolin. We will then begin studies to identify factor(s) that are responsible for the spatial specific development of otoconia. These studies will define the roles of and provide a mechanism for some critical components in determining otoconia formation.
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