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Matrix Otopathology

矩阵耳病理学

基本信息

批准号：
7321275
负责人：
Michael Anne NMI Gratton
金额：
$ 34.09万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-01-01 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7321275
关键词：
Adult Affect Age Agonist Animal Model Auditory Auditory Brainstem Responses Award Basement membrane Bioenergetics Biological Assay Biological Markers Birth Blood capillaries Cell Adhesion Process Cell Maturation Cochlea Cochlear duct Collagen Type IV Condition Control Groups Cultured Cells Data Deterioration Development Diabetes Mellitus Disease Dyes Ear Energy Metabolism Epithelial Exhibits Exposure to Extracellular Matrix Functional disorder Funding Gene Expression Gene Expression Regulation Gene Proteins Genes Goals Hereditary Disease Hereditary nephritis Homeostasis Human Hypoxia Hypoxia Inducible Factor Immunohistochemistry In Vitro Inherited Inorganic Sulfates Ion Transport Kidney Failure Labyrinth Lateral Ligaments Link Location Masks Matrix Metalloproteinases Measures Membrane Membrane Proteins Metabolic Metabolism Modeling Molecular Mouse Strains Mus Mutation NMI gene Na(+)-K(+)-Exchanging ATPase Noise Oxygen measurement, partial pressure, arterial Pathology Peripheral Permeability Play Polymerase Chain Reaction Presbycusis Production Property Protein Binding Protein Isoforms Proteins RNA Reactive Oxygen Species Regulation Research Research Design Research Personnel Role Signal Pathway Site Stress Stria Vascularis Supporting Cell Systemic Lupus Erythematosus Techniques Testing Thick Thinking Tight Junctions Time Tissues Tracer Unspecified or Sulfate Ion Sulfates Vascular Endothelial Growth Factor Receptor Week Western Blotting Wild Type Mouse acetovanillone analog capillary cell motility day deafness design diacetyldichlorofluorescein diphenyleneiodonium hearing impairment human NMI protein in vivo inhibitor/antagonist interest membrane synthesis middle ear mouse model otoacoustic emission programs research study response sound

项目摘要

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.

描述（由申请人提供）：耳蜗中的特化上皮细胞和支持细胞与细胞外基质密切相关。一种这样的基质，即基底膜，利用IV型胶原形成独特的蛋白质晶格，其他基质蛋白质与之结合。在发育过程中，基底膜在细胞迁移和细胞成熟中起关键作用，而在成熟组织中，它们有助于细胞粘附、极化和渗透性过程。基底膜在成熟耳蜗中的作用仍有待充分描述。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厚的毛细血管基底膜和听觉功能障碍。Alport综合征的动物模型特别令人感兴趣，因为它是由编码IV型胶原蛋白的基因突变引起的。目前的建议是确定增厚的毛细血管基底膜是如何导致听觉功能异常的。异常基底膜和听力损失之间的关系进行了探讨，通过确定的后果基底膜积累外周听觉功能;评估缺氧相关的反应，基底膜积累;和改善缺氧和听觉功能障碍的抑制毛细血管基底膜积累。本文提出了两个假说：1）耳蜗组织基底膜的异常导致耳蜗代谢稳态的恶化，从而降低耳蜗功能。这一假设是通过用强烈但非破坏性的声音刺激耗尽人体的能量储备来检验的。暴露后，外周听觉功能以及血管纹的电化学和离子传输特性的方面进行测量，以确定纹和中阶的动态平衡的变化。2)基底膜蛋白的积累上调缺氧相关的反应，调节与基底膜稳态相关的基因。这一假设是通过定量的表达缺氧相关的基因和蛋白质的纹进行评估。通过测量耳蜗毛细血管基底膜厚度、耳蜗内电位和耳蜗氧分压来评估旨在逆转基底膜积聚的药理学操作。这些实验的结果提供了一个明确的图片的作用，异常基底膜发挥听觉功能障碍叙述：该项目评估的作用，基底膜在内耳。这项研究是在一只内耳毛细血管基底膜增厚的老鼠身上进行的。小鼠用作基底膜异常的模型，因此获得的数据将与具有增厚的毛细血管基底膜和听力损失的其他疾病状况相关。