Specialized epithelial and supporting cells in the cochlea are closely associated with extracellular matrices. One such matrix, the basement membrane, utilizes type IV collagen to form a unique protein lattice to which other matrix proteins bind. During development, basement membranes play a critical role in cell migration and cell maturation, while in mature tissue they contribute to processes of cell adhesion, polarization and permeability. The role of basement membranes in the mature cochlea remains to be fully described. Nevertheless, animal models of diabetes mellitus, systemic lupus erythematosus, presbycusis, and Alport's syndrome exhibit abnormally thick strial capillary basement membranes and auditory dysfunction. The animal model of Alport's syndrome is of particular interest since it arises from a mutation in the gene encoding type IV collagen. The current proposal determines how thickened strial capillary basement membranes contribute to abnormal auditory function. The relationship between abnormal basement membranes and hearing loss is explored by determining the consequences of basement membrane accumulation on peripheral auditory function; evaluating hypoxia-related responses to basement membrane accumulation; and amelioration of hypoxia and auditory dysfunction by inhibition of strial capillary basement membrane accumulation. Experiments are proposed to test the validity of two hypotheses: 1) The abnormal basement membranes in strial tissue result in a deterioration of metabolic homeostasis in the cochlea that degrades cochlear function. This hypothesis is tested by depleting strial energy reserves with intense, but non-damaging, sound stimulation. Following exposure, aspects of peripheral auditory function as well as the electrochemical and ion transport properties of the stria vascularis are measured to determine changes in the homeostasis of the stria and scala media. 2) The accumulation of basement membrane proteins upregulate hypoxia-related responses that modulate genes associated with basement membrane homeostasis. This hypothesis is evaluated by quantifying the expression of hypoxia-related genes and proteins in the stria. Pharmacological manipulations designed to reverse basement membrane accumulation are evaluated by measuring strial capillary basement membrane thickness, the endocochlear potential, and cochlear oxygen tension. The results of these experiments provide a definitive picture of the role that abnormal basement membranes play in auditory dysfunction Narrative: This project evaluates the role of basement membranes in the inner ear. The research is performed in a mouse whose inner ear has thickened strial capillary basement membranes. The mouse serves as a model of basement membrane abnormality and therefore data obtained will be relevant to other disease conditions which have thickened strial capillary basement membranes and hearing loss. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
7R01DC006442-06
Application #
7878255
Study Section
Auditory System Study Section (AUD)
Program Officer
Cyr, Janet
Project Start
2004-01-01
Project End
2012-08-31
Budget Start
2009-04-01
Budget End
2009-08-31
Support Year
6
Fiscal Year
2008
Total Cost
$173,730
Indirect Cost
Name
Saint Louis University
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
050220722
City
Saint Louis
State
MO
Country
United States
Zip Code
63103
Dufek, Brianna; Meehan, Daniel T; Delimont, Duane et al. (2016) Endothelin A receptor activation on mesangial cells initiates Alport glomerular disease. Kidney Int 90:300-310
Gasser Rutledge, Krysta L; Prasad, Kumar G; Emery, Kara R et al. (2015) Short-term Peripheral Auditory Effects of Cranial Irradiation: A Mouse Model. Ann Otol Rhinol Laryngol 124:903-10
Delimont, Duane; Dufek, Brianna M; Meehan, Daniel T et al. (2014) Laminin ?2-mediated focal adhesion kinase activation triggers Alport glomerular pathogenesis. PLoS One 9:e99083
Zallocchi, Marisa; Meehan, Daniel T; Delimont, Duane et al. (2012) Role for a novel Usher protein complex in hair cell synaptic maturation. PLoS One 7:e30573
Cosgrove, Dominic (2012) Glomerular pathology in Alport syndrome: a molecular perspective. Pediatr Nephrol 27:885-90
Gratton, Michael Anne; Eleftheriadou, Anna; Garcia, Jerel et al. (2011) Noise-induced changes in gene expression in the cochleae of mice differing in their susceptibility to noise damage. Hear Res 277:211-26
Zallocchi, Marisa; Meehan, Daniel T; Delimont, Duane et al. (2009) Localization and expression of clarin-1, the Clrn1 gene product, in auditory hair cells and photoreceptors. Hear Res 255:109-20
Nie, Liping; Zhu, Jun; Gratton, Michael Anne et al. (2008) Molecular identity and functional properties of a novel T-type Ca2+ channel cloned from the sensory epithelia of the mouse inner ear. J Neurophysiol 100:2287-99
Bedrosian, Jeffrey C; Gratton, Michael Anne; Brigande, John V et al. (2006) In vivo delivery of recombinant viruses to the fetal murine cochlea: transduction characteristics and long-term effects on auditory function. Mol Ther 14:328-35
Rao, Velidi H; Meehan, Daniel T; Delimont, Duane et al. (2006) Role for macrophage metalloelastase in glomerular basement membrane damage associated with alport syndrome. Am J Pathol 169:32-46

Showing the most recent 10 out of 13 publications