While 50% of the US population experiences balance problems at some point during their lifetime, there is no currently NIH funded research program focused on gene discovery in the vestibular periphery. Until we know the transcriptome associated with the cell types comprising the vestibular end organs, we will not fully understand the complexity of the system and we will be missing opportunities for drug development to help our children and adults with balance problems. The objective of this research program is to understand the projection of the vestibular efferent neurons to the vestibular periphery in the context of the fundamental molecular sensory organization of the receptors and the vestibular primary afferent neurons. By defining the molecular basis of the efferent/afferent interaction, a clear mechanistic understanding of function will emerge that should provide valuable insight into the causes of disease states associated with balance disorders. This will not only facilitate the development of new drugs to treat our patients with vestibular dysfunction, but will likely lead to the identification of candidate genes and alternatively spliced transcripts that result in vestibular disease. This continuation proposal seeks funding to address four questions that are all focused on providing a functional prediction of the efferent/afferent interaction: 1) What are the genes subserving the efferent/afferent interaction in anatomically and immunohistochemically defined cell types in the vestibular periphery?; 2) Are the muscarinic acetylcholine receptor subtypes 2 and 4 found in the crista ampullaris functional?; 3) Since potassium channels probably are responsible for much of the heterogeneity in afferent and efferent signaling, what are their topographical and cellular locations throughout the vestibular epithelia?; and 4) What are the locations of selected identified proteins and mRNAs subserving the efferent/afferent interaction identified in the previous funding period and during the execution of Aim 1? Once these questions are answered, models for determining the role of the efferent and afferent pathways during vestibular compensation, following vestibular injury, or in specific vestibular disorders such as Meniere's disease or genetic vestibulopathies can be developed. It is likely that completion of these aims will not only provide a clear understanding of the genes responsible for the efferent/afferent interaction, but will benefit other neuroscientists and clinicians who are interested in basic inner ear biology and who work for the benefit of our patients with hearing and balance disorders. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC002971-12
Application #
7207989
Study Section
Auditory System Study Section (AUD)
Program Officer
Platt, Christopher
Project Start
1995-07-01
Project End
2009-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
12
Fiscal Year
2007
Total Cost
$499,841
Indirect Cost
Name
Medical College of Wisconsin
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
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Popper, Paul; Winkler, John; Erbe, Christy B et al. (2008) Distribution of two-pore-domain potassium channels in the adult rat vestibular periphery. Hear Res 246:1-8
Cioffi, Joseph A; Wackym, P Ashley; Erbe, Christy B et al. (2005) Molecular characterization of two novel splice variants of G alphai2 in the rat vestibular periphery. Brain Res Mol Brain Res 137:89-97
Roche, Joseph P; Wackym, P Ashley; Cioffi, Joseph A et al. (2005) In silico analysis of 2085 clones from a normalized rat vestibular periphery 3' cDNA library. Audiol Neurootol 10:310-22
Cristobal, Ricardo; Wackym, P Ashley; Cioffi, Joseph A et al. (2005) Assessment of differential gene expression in vestibular epithelial cell types using microarray analysis. Brain Res Mol Brain Res 133:19-36
Wackym, P Ashley; Cioffi, Joseph A; Erbe, Christy B et al. (2005) G-protein Golfalpha (GNAL) is expressed in the vestibular end organs and primary afferent neurons of Rattus norvegicus. J Vestib Res 15:11-5
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Cristobal, Ricardo; Wackym, P Ashley; Cioffi, Joseph A et al. (2004) Selective acquisition of individual cell types in the vestibular periphery for molecular biology studies. Otolaryngol Head Neck Surg 131:590-5
Cioffi, Joseph A; Erbe, Christy B; Raphael, Richard et al. (2003) Expression of G-protein alpha subunit genes in the vestibular periphery of Rattus norvegicus and their chromosomal mapping. Acta Otolaryngol 123:1027-34
Halum, Stacey L; Erbe, Christy B; Friedland, David R et al. (2003) Gene discovery using a human vestibular schwannoma cDNA library constructed from a patient with neurofibromatosis type 2 (NF2). Otolaryngol Head Neck Surg 128:364-71

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