Genetic basis for gravity receptor dysfunction in mice

Project: Research project

Description

DESCRIPTION (provided by applicant): 3.4% of the US adult population, or 6.2 million individuals, experience chronic dizziness and/or imbalance. While the prevalence of these conditions is greater among older adults, balance problems can occur at any age. The cause of dizziness/imbalance often remains unknown and treatment may often be unsuccessful. Could there be a genetic basis for dizziness/imbalance in some of these individuals? While much is being learned about the genetics of deafness, relatively little is known about the role genes may play in vestibular dysfunction (i.e., vestibular impairment occurring in the absence of significant hearing loss). Not all genetic mutations produce both cochlear and vestibular abnormalities. Otoconia-deficient mice (e.g., het, tit) are examples of selective vestibular impairment due to genetic mutations. Preliminary data have identified inbred mouse strains with early onset, profound macular deficits and normal hearing. Our hypothesis is that genetic mutations exist, which produce selective, hereditary vestibular impairment. Furthermore, we hypothesize that the selective vestibular impairment is due to deficits other than otoconial loss. The proposed research will test these hypotheses. Specific Aim 1 will identify inbred strains that exhibit gravity receptor impairment by 3 months of age. We will record linear vestibular evoked potentials (VsEPs) and auditory brainstem responses (ABR) in age matched animals to determine the functional status of the macular and auditory organs, respectively. Specific aim 2 will characterize gravity receptor function in relation to age in those strains identified with vestibular impairment in specific aim 1. VsEPs will be collected at several ages to describe the time course and nature of the macular deficit. ABRs will be collected to confirm the absence of significant hearing impairment. Specific aim 3 will examine end organ and primary afferent anatomy to identify putative structural correlates for the functional deficits evaluated in specific aim 2. We will examine morphological features of hair cell stereocilia and bundles, the numbers and distributions of hair cell types, key structures at synapses and the relative number, size and distribution of afferent neurons. Specific aim 4 will map loci that contribute to gravity receptor dysfunction using genome-wide linkage analyses of two inbred strain backcrosses. This research will extend our understanding of vestibular ontogeny and vestibular dysfunction. In addition, we will identify loci for hereditary vestibular impairment providing the basis for identifying specific genes affecting the vestibular system and, potentially, genetic homologs for human vestibular disease. This work may lead to better diagnosis and treatment of vestibular impairment.
StatusFinished
Effective start/end date12/15/0511/30/11

Funding

  • National Institutes of Health: $273,347.00
  • National Institutes of Health: $306,160.00
  • National Institutes of Health: $279,743.00
  • National Institutes of Health: $276,107.00
  • National Institutes of Health: $175,595.00
  • National Institutes of Health: $276,107.00

Fingerprint

Gravitation
Dizziness
Hearing Loss
Stereocilia
Otolithic Membrane
Evoked Potentials
Afferent Neurons
Cochlea
Deafness
Mutation
Research
Synapses
Hearing
Genes
Auditory Evoked Potentials
Anatomy
Genome
Vestibular Diseases
Population
Inbred Strains Mice

ASJC

  • Medicine(all)
  • Neuroscience(all)