Hair cells show a remarkable variability in their membrane conductances along the tonotopic axis of a hearing organ. The long-term objectives are to determine the molecular basis for this heterogeneity and to ascertain the mechanisms responsible for its generation and maintenance. Using the chick basilar papilla as a model system, Dr. Oberholtzer has cloned four potassium channel genes, three of which (cSlo, cIRK1, and cKv3.1) encode channels previously shown to be differentially distributed. cSlo is extensively alternatively spliced, providing one mechanism for the functional heterogeneity of BK potassium currents carried by the channel gene's gene product. To determine how cSlo heterogeneity supports frequency cloning, the investigators will determine the native cSlo transcript isoforms that are expressed in the basilar papilla. Because the functional properties of cSlo may be modified by cSlack, they will determine the functional properties of cSlack alone and in combination with cSlo. Heterogeneity in expression of cIRK1 and cKv3.1 in the basilar papilla does not arise from alternative splicing, but rather by selective expression only in the apical half of the papilla. To dissect the mechanism involved in tonotopic expression restriction, the investigators will characterize in vitro the promoter and upstream sequences of cIRK1 that may play a role in expression restriction. To extend these studies into the context of native hair-cell chromatin, the investigators will determine in vivo the relevance of candidate cIRK1 5'-flanking control regions by analyzing the endogenous locus. The results obtained should provide insight to those interested in peripheral auditory system function, as well as to those interested in understanding mechanisms of gene regulation.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC002755-09
Application #
6693424
Study Section
Special Emphasis Panel (ZRG1-IFCN-6 (01))
Program Officer
Donahue, Amy
Project Start
1995-08-01
Project End
2005-11-30
Budget Start
2003-12-01
Budget End
2004-11-30
Support Year
9
Fiscal Year
2004
Total Cost
$317,031
Indirect Cost
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Mutai, Hideki; Kenyon, Lawrence C; Locke, Emily et al. (2004) Characterization of the chicken inward rectifier K+ channel IRK1/Kir2.1 gene. BMC Genomics 5:90
Hiel, Hakim; Navaratnam, Dasakumar S; Oberholtzer, John C et al. (2002) Topological and developmental gradients of calbindin expression in the chick's inner ear. J Assoc Res Otolaryngol 3:1-15
Navaratnam, D S; Bell, T J; Tu, T D et al. (1997) Differential distribution of Ca2+-activated K+ channel splice variants among hair cells along the tonotopic axis of the chick cochlea. Neuron 19:1077-85
Navaratnam, D S; Su, H S; Scott, S P et al. (1996) Proliferation in the auditory receptor epithelium mediated by a cyclic AMP-dependent signaling pathway. Nat Med 2:1136-9