Matrix Otopathology

矩阵耳病理学

• 批准号: 6709487
• 负责人: Michael Anne NMI Gratton
• 金额: $ 32.73万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6709487
• 关键词: Alport syndrome; adenosine triphosphate; basement membrane; brain electrical activity; cochlea; collagen; disease /disorder model; extracellular matrix; laboratory mouse; laminin; membrane permeability; membrane potentials; noise biological effect; pathologic process; protein metabolism; proteoglycan; sodium potassium exchanging ATPase; tissue /cell culture

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.

描述（由申请人提供）：基底膜是一种独特的细胞外基质类型，它是Scala培养基的专门上皮和支持细胞的基础，并包围了内皮细胞和神经元。在耳蜗/发育过程中，基底膜在细胞迁移和分化中起关键作用。但是，尚未研究人工耳蜗基底膜的作用。在其他成熟的组织中，基底膜参与细胞粘附和极化以及组织渗透性。地下膜形成需要组装IV型胶原蛋白晶格。其他地下膜蛋白与胶原蛋白晶格结合。编码IV型胶原蛋白同工型的基因中的突变导致Alport综合征，Alport综合征表现出对听觉，视觉和肾脏系统的进行性功能障碍的疾病。 Alport综合征的小鼠模型表现出增厚的脊柱毛细血管基底膜。利用Alport小鼠来实现该提案的总体目标，即对成年耳蜗的基底膜功能的理解。具体而言，我们专注于基质厚度的影响，然后研究控制基质积累的机制。实验旨在检验三个一般假设：1）在基质眼病理学中降低了肺活能代谢。通过表征丝质的电化学和运输特性来探索噪声暴露后枯竭的静电能量产生的后果。 2）基质眼病理学增加了地下室膜蛋白聚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）当合成上调超过胶原蛋白和层粘连蛋白的降解时，基质会累积。量化了基因和控制基底膜合成和降解的蛋白质表达的变化。 拟议的工作阐明了基底膜与静脉功能和正常听力的关系。