This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Otoconia, crystallites of CaCO3 and proteins, are required for an individual to sense linear acceleration and gravity for spatial orientation and balance control. Dysfunction of this system is a critical clinical problem, particulady in the elderly, yet little is known about the mechanisms that regulate otoconial biosynthesis. Otoconia appear to be in a dynamic state of equilibrium highly susceptible to adverse effects of aging, infections, diseases and genetic mutations, but the molecular mechanisms of these problems are largely unknown. Our overall hypotheses are that (1) the interplay of multiple specific protein components of otoconia and their embedding membrane determines their site-specific formation; (2) Otoconial protein homeostasis is essential to normal otoconia function; and (3) OC90, a major protein component of otoconia, is essential for the formation of otoconia by sequestering Ca. OC90 mutant mice will manifest a functional deficit of the inner ear, with the vestibule as the focus of this proposal. Specifically in this proposal, we will (1) identify other murine otoconial proteins and their cellular origin, to help identify factors that may contribute to otoconia formation. We will identify any interactions among OC90, otogelin, and other proteins in otoconia, its embedding membrane or the sensory epithelium by co-precipitation on PS10 protein chips to test hypothesis #1. (2) We will examine whether disrupted otoconin homeostasis caused the abnormal and malfunctioning otoconia in aging (C57BI/6J) and degenerating otoconia (head-tilt mice) by protein profiling on H4 chips, and examine changes in the deposition of otoconial proteins in embryos and newborn pups that have disrupted calcium homeostasis (tilt, PMCA-/- mice). (3) Then we will test hypothesis #3 by examining the spatial coordination of OC90 expression and Ca transportation, and by making two mutant mouse lines, one null and the other carting only one functional (PLA2L) domain, to study the role of OC90 in otoconia formation and gravity sensing, as well as in cochlea function. Combined with future sophisticated behavioral, physiological and gene/protein profiling studies, we will demonstrate the role of OC90 in bodily balancing, the molecular mechanisms of site-specific formation, regulation and proper maintenance of otoconia. Thus we will contribute to understanding inner ear development, function, physiology and pathology.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Exploratory Grants (P20)
Project #
5P20RR018788-04
Application #
7382086
Study Section
Special Emphasis Panel (ZRR1-RI-3 (01))
Project Start
2006-05-01
Project End
2007-04-30
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
4
Fiscal Year
2006
Total Cost
$273,098
Indirect Cost
Name
University of Nebraska Medical Center
Department
Pediatrics
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
Barta, Cody L; Liu, Huizhan; Chen, Lei et al. (2018) RNA-seq transcriptomic analysis of adult zebrafish inner ear hair cells. Sci Data 5:180005
Sanchez, Sonia M Rocha; Fuson, Olivia; Tarang, Shikha et al. (2018) Quinoxaline protects zebrafish lateral line hair cells from cisplatin and aminoglycosides damage. Sci Rep 8:15119
Liu, Huizhan; Chen, Lei; Giffen, Kimberlee P et al. (2018) Cell-Specific Transcriptome Analysis Shows That Adult Pillar and Deiters' Cells Express Genes Encoding Machinery for Specializations of Cochlear Hair Cells. Front Mol Neurosci 11:356
Gong, Qiang; Wang, Chao; Zhang, Weiwei et al. (2017) Assessment of T-cell receptor repertoire and clonal expansion in peripheral T-cell lymphoma using RNA-seq data. Sci Rep 7:11301
Olivares, A M; Jelcick, A S; Reinecke, J et al. (2017) Multimodal Regulation Orchestrates Normal and Complex Disease States in the Retina. Sci Rep 7:690
Goodman, Linda; Zallocchi, Marisa (2017) Integrin ?8 and Pcdh15 act as a complex to regulate cilia biogenesis in sensory cells. J Cell Sci 130:3698-3712
Bouska, A; Zhang, W; Gong, Q et al. (2017) Combined copy number and mutation analysis identifies oncogenic pathways associated with transformation of follicular lymphoma. Leukemia 31:83-91
Donze-Reiner, Teresa; Palmer, Nathan A; Scully, Erin D et al. (2017) Transcriptional analysis of defense mechanisms in upland tetraploid switchgrass to greenbugs. BMC Plant Biol 17:46
Amaradasa, Bimal S; Amundsen, Keenan (2016) Transcriptome Profiling of Buffalograss Challenged with the Leaf Spot Pathogen Curvularia inaequalis. Front Plant Sci 7:715
Rohr, J; Guo, S; Huo, J et al. (2016) Recurrent activating mutations of CD28 in peripheral T-cell lymphomas. Leukemia 30:1062-70

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