Matrix Otopathology

描述(申请人提供)：耳蜗内的特化上皮细胞和支持细胞与细胞外基质密切相关。一个这样的基质，基底膜，利用IV型胶原形成一个独特的蛋白质晶格，其他基质蛋白与之结合。在发育过程中，基底膜在细胞迁移和细胞成熟过程中起关键作用，而在成熟组织中，基底膜参与细胞黏附、极化和通透性的过程。基底膜在成熟耳蜗组织中的作用仍有待充分研究。然而，糖尿病、系统性红斑狼疮、老年性耳聋和Alport综合征的动物模型表现出异常增厚的毛细血管基底膜和听觉功能障碍。阿尔波特综合征的动物模型特别令人感兴趣，因为它是由编码IV型胶原的基因突变引起的。目前的建议确定了增厚的工业毛细血管基底膜如何促进异常的听觉功能。通过确定基底膜积聚对周围听功能的影响，评估基底膜积聚对低氧的相关反应，以及通过抑制毛细血管基底膜积聚来改善低氧和听力功能障碍，探讨基底膜异常与听力损失的关系。实验旨在验证两个假说的正确性：1)工业组织中的基底膜异常导致耳蜗代谢动态平衡的恶化，从而降低耳蜗的功能。这一假设是通过用强烈但非破坏性的声音刺激来耗尽能源储备来检验的。暴露后，测量周围听觉功能的方面以及血管纹的电化学和离子传输特性，以确定纹状体和中阶骨的内稳态的变化。2)基底膜蛋白的积累上调了与缺氧相关的反应，从而调节了与基底膜动态平衡相关的基因。这一假说是通过量化与缺氧相关的基因和蛋白在纹状体中的表达来评估的。旨在逆转基底膜蓄积的药物操作通过测量工业毛细血管基底膜厚度、耳蜗内电位和耳蜗氧分压来评估。这些实验的结果为异常基底膜在听觉功能障碍叙事中所起的作用提供了一个明确的图景：这个项目评估了基底膜在内耳中的作用。这项研究是在一只内耳毛细血管基底膜增厚的小鼠身上进行的。小鼠作为基底膜异常的模型，因此获得的数据将与其他疾病相关，这些疾病包括毛细血管基底膜增厚和听力损失。

DESCRIPTION (provided by applicant): 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.