Matrix Otopathology

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DESCRIPTION (provided by applicant): 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.