Abstract

Basement membrane is a unique type of extracellular matrix that underlies the specialized epithelial and supporting cells of the scala media and surrounds endothelial cells and neurons. During cochlea/development, basement membranes play a critical role in cell migration and differentiation. However, the role of cochlear basement membranes post-development has not been studied. In other mature tissues, basement membranes are involved in cell adhesion and polarization as well as tissue permeability. Basement membrane formation requires assembly of a type IV collagen lattice. Other basement membrane proteins bind to the collagen lattice. A mutation in a gene encoding a type IV collagen isoform results in Alport syndrome, a disorder exhibiting progressive dysfunction of the auditory, visual and renal systems. The mouse model of Alport syndrome exhibits thickened strial capillary basement membranes. The Alport mouse is exploited to achieve the overall goal of this proposal, namely an understanding of basement membrane function in the adult cochlea. Specifically we focus on the impact of matrix thickness followed by investigation of the mechanisms controlling matrix accumulation. Experiments are designed to test three general hypotheses: 1) Strial energy metabolism is reduced in matrix otopathology. The consequences of depleted strial energy production following noise exposure are explored by characterizing electrochemical and transport properties of the stria. 2) The anionic barrier provided by basement membrane proteoglycans is increased by matrix otopathology. The proteoglycan composition of the lateral wall basement membranes is quantified with cationic probes. 3) Matrix accumulates when upregulation of synthesis exceeds degradation in collagen and laminin. Changes in the expression of genes and proteins controlling basement membrane synthesis and degradation are quantified. The proposed work clarifies the relationship of basement membrane to strial function and normal hearing.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
1R01DC006442-01
Application #
6709487
Study Section
Integrative, Functional and Cognitive Neuroscience 8 (IFCN)
Program Officer
Donahue, Amy
Project Start
2004-01-01
Project End
2006-12-31
Budget Start
2004-01-01
Budget End
2004-12-31
Support Year
1
Fiscal Year
2004
Total Cost
$327,316
Indirect Cost

  Institution

Name
University of Pennsylvania
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104

  Publications

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