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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
3R01DC008603-04S1
Application #
8208328
Study Section
Auditory System Study Section (AUD)
Program Officer
Freeman, Nancy
Project Start
2007-07-01
Project End
2012-06-30
Budget Start
2011-01-01
Budget End
2011-06-30
Support Year
4
Fiscal Year
2011
Total Cost
$45,260
Indirect Cost
Name
Father Flanagan's Boys' Home
Department
Type
DUNS #
073136806
City
Boys Town
State
NE
Country
United States
Zip Code
68010
Xu, Yinfang; Zhang, Yan; Lundberg, Yunxia Wang (2016) Spatiotemporal differences in otoconial gene expression. Genesis 54:613-625
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
Lundberg, Yunxia Wang; Xu, Yinfang; Thiessen, Kevin D et al. (2015) Mechanisms of otoconia and otolith development. Dev Dyn 244:239-53
Ogun, Oluwaseye Ayoola; Janky, Kristen L; Cohn, Edward S et al. (2014) Gender-based comorbidity in benign paroxysmal positional vertigo. PLoS One 9:e105546
Ogun, Oluwaseye Ayoola; Büki, Bela; Cohn, Edward S et al. (2014) Menopause and benign paroxysmal positional vertigo. Menopause 21:886-9
Buki, Bela; Ecker, Michael; Junger, Heinz et al. (2013) Vitamin D deficiency and benign paroxysmal positioning vertigo. Med Hypotheses 80:201-4
Kim, Euysoo; Hyrc, Krzysztof L; Speck, Judith et al. (2011) Missense mutations in Otopetrin 1 affect subcellular localization and inhibition of purinergic signaling in vestibular supporting cells. Mol Cell Neurosci 46:655-61
Deng, Fei-Yan; Lei, Shu-Feng; Zhang, Yan et al. (2011) Peripheral blood monocyte-expressed ANXA2 gene is involved in pathogenesis of osteoporosis in humans. Mol Cell Proteomics 10:M111.011700
Büki, Béla; Simon, László; Garab, Sándor et al. (2011) Sitting-up vertigo and trunk retropulsion in patients with benign positional vertigo but without positional nystagmus. J Neurol Neurosurg Psychiatry 82:98-104
Yang, Hua; Zhao, Xing; Xu, Yinfang et al. (2011) Matrix recruitment and calcium sequestration for spatial specific otoconia development. PLoS One 6:e20498

Showing the most recent 10 out of 15 publications