Problems with balance are a leading cause of death and injury in elderly populations. Despite the prevalence of this problem little is known about the molecular mechanisms regulating vestibular development and pathology. Well characterized mouse mutants and techniques for sequencing small amounts of protein provide a means to clone genes that are expressed in the vestibular system. In turn allowing a biochemical and genetic analysis and an understanding of the molecular mechanisms underlying vestibular pathophysiology. We have characterized a mouse mutant (tilted) that is missing vestibular otoconia but that has an apparently normal sensory epithelium. We have also cloned the major matrix protein of mammalian otoconia, otoconin-90 (OC90), and showed that it is expressed in non-sensory vestibular epithelium during development in both control and tilted mice. We hypothesize that the mutation in the tilted mouse results in a missing or defective protein that is involved in the biosynthesis or structure of otoconia, or that is involved in the regulation of expression of other vestibular genes. Other otoconins may therefore also be missing, misexpressed or incorrectly modified secondary to the tilted mutation. We are using the tilted mouse mutant to facilitate the identification of genes responsible for otoconial biosynthesis. In this proposal we will: 1) Identify the mutant gene responsible for the tilted phenotype by positional cloning. 2) Identify and clone protein constituents of the otoconial complex. 3) Determine the spatial and developmental expression of the Oc90 gene and protein in wild type, tilted and head tilt mice (Testing the hypothesis that glycosylation or processing of OC90 is altered in these mouse mutants). The unprecedented structural features and the unexpected expression pattern of Oc90 has provided valuable insights into the mechanisms of otoconial formation and provide us with molecular and biochemical tools to elucidate unresolved areas of otoconial biology and pathophysiology, including turnover of otoconia and their organic and inorganic phases, degeneration, repair and regeneration. Human otoconia are subject to aging, drug and disease related pathology. In combination with age-related degeneration of sensory cells, these dysfunctions contribute significantly to the susceptibility of aged individuals to falling. In postmenopausal women this danger is compounded by osteoporosis, with the sequela of bone fracture. In 1991 medical care for treating individuals with balance related disorders cost 1 billion dollars per year.
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