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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC006443-05
Application #
7727924
Study Section
Auditory System Study Section (AUD)
Program Officer
Watson, Bracie
Project Start
2005-12-15
Project End
2011-11-30
Budget Start
2009-12-01
Budget End
2011-11-30
Support Year
5
Fiscal Year
2010
Total Cost
$273,347
Indirect Cost
Name
East Carolina University
Department
Other Health Professions
Type
Schools of Allied Health Profes
DUNS #
607579018
City
Greenville
State
NC
Country
United States
Zip Code
27858
Vijayakumar, Sarath; Lever, Teresa E; Pierce, Jessica et al. (2015) Vestibular dysfunction, altered macular structure and trait localization in A/J inbred mice. Mamm Genome 26:154-72
Jones, Timothy A; Lee, Choongheon; Gaines, G Christopher et al. (2015) On the high frequency transfer of mechanical stimuli from the surface of the head to the macular neuroepithelium of the mouse. J Assoc Res Otolaryngol 16:189-204
Jones, Sherri M; Jones, Timothy A (2014) Genetics of peripheral vestibular dysfunction: lessons from mutant mouse strains. J Am Acad Audiol 25:289-301
Mendus, Diana; Sundaresan, Srividya; Grillet, Nicolas et al. (2014) Thrombospondins 1 and 2 are important for afferent synapse formation and function in the inner ear. Eur J Neurosci 39:1256-67
Lee, Sue I; Conrad, Travis; Jones, Sherri M et al. (2013) A null mutation of mouse Kcna10 causes significant vestibular and mild hearing dysfunction. Hear Res 300:1-9
Gaines, G Christopher; Jones, Timothy A (2013) Effects of acute administration of ketorolac on mammalian vestibular sensory evoked potentials. J Am Assoc Lab Anim Sci 52:57-62
Nayak, Gowri; Lee, Sue I; Yousaf, Rizwan et al. (2013) Tricellulin deficiency affects tight junction architecture and cochlear hair cells. J Clin Invest 123:4036-49
Goodyear, Richard J; Jones, Sherri M; Sharifi, Louise et al. (2012) Hair bundle defects and loss of function in the vestibular end organs of mice lacking the receptor-like inositol lipid phosphatase PTPRQ. J Neurosci 32:2762-72
Jones, Timothy A; Jones, Sherri M; Vijayakumar, Sarath et al. (2011) The adequate stimulus for mammalian linear vestibular evoked potentials (VsEPs). Hear Res 280:133-40
Jones, Sherri M; Robertson, Nahid G; Given, Shelly et al. (2011) Hearing and vestibular deficits in the Coch(-/-) null mouse model: comparison to the Coch(G88E/G88E) mouse and to DFNA9 hearing and balance disorder. Hear Res 272:42-8

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