Matrix Otopathology

描述（由申请人提供）：基底膜是一种独特类型的细胞外基质，位于中阶的特化上皮细胞和支持细胞之下，并包围内皮细胞和神经元。在耳蜗发育过程中，基底膜在细胞迁移和分化中起着关键作用。然而，耳蜗基底膜后发育的作用还没有研究。在其他成熟组织中，基底膜参与细胞粘附和极化以及组织渗透性。基底膜的形成需要IV型胶原晶格的组装。其他基底膜蛋白质结合到胶原晶格。编码IV型胶原蛋白同种型的基因突变导致Alport综合征，这是一种表现出听觉、视觉和肾脏系统进行性功能障碍的疾病。Alport综合征小鼠模型显示毛细血管基底膜增厚。利用Alport小鼠来实现本提案的总体目标，即了解成年耳蜗中的基底膜功能。具体来说，我们专注于矩阵厚度的影响，其次是调查控制矩阵积累的机制。实验设计来检验三个一般性假设：1）基质耳病理学中的能量代谢减少。耗尽的噪音暴露后的能量生产的后果进行了探讨，通过表征电化学和运输性能的条纹。2)基质耳病理学增加了基底膜蛋白多糖提供的阴离子屏障。用阳离子探针定量侧壁基底膜的蛋白聚糖组成。3)当胶原蛋白和层粘连蛋白的合成上调超过降解时，基质积聚。定量控制基底膜合成和降解的基因和蛋白质表达的变化。 这项工作阐明了基底膜与听觉功能和正常听力的关系。

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.