Matrix Otopathology

描述(申请人提供)：基底膜是一种独特的细胞外基质，位于中阶的特殊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过程中起着至关重要的作用。然而，耳蜗基底膜在发育后期的作用尚未得到研究。在其他成熟组织中，基底膜参与了细胞的黏附和极化以及组织的通透性。基底膜的形成需要IV型胶原网的组装。其他基底膜蛋白与胶原蛋白晶格结合。编码IV型胶原亚型的基因突变导致Alport综合征，这是一种表现为听觉、视觉和肾脏系统进行性功能障碍的疾病。Alport综合征小鼠模型表现为毛细血管基底膜增厚。利用Alport小鼠来实现这一建议的总体目标，即了解成人耳蜗基底膜的功能。具体地说，我们重点研究了基质厚度的影响，然后研究了控制基质积累的机制。实验旨在验证三个普遍的假设：1)基质耳病理学中的工业能量代谢降低。通过表征条纹的电化学性质和传输特性，探讨了噪声暴露后耗尽的工业能量产生的后果。2)基质病理改变增加了基底膜蛋白多糖提供的阴离子屏障。用阳离子探针定量测定侧壁基底膜的蛋白多糖组成。3)当合成的上调超过胶原和层粘连蛋白的降解时，基质堆积。对控制基底膜合成和降解的基因和蛋白质的表达变化进行了量化。 这项工作阐明了基底膜与工业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.