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）：耳蜗中的专门上皮和支持细胞与细胞外基质密切相关。一个这样的基质（地下室膜）利用IV型胶原蛋白形成独特的蛋白质晶格，其他基质蛋白与该蛋白质结合。在发育过程中，基底膜在细胞迁移和细胞成熟中起着至关重要的作用，而在成熟的组织中，它们有助于细胞粘附，极化和渗透率的过程。地下膜在成熟的耳蜗中的作用尚待充分描述。然而，糖尿病的动物模型，全身性红斑狼疮，长老会和Alport综合征表现出异常厚的脊柱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。当前的提案确定了增厚毛细血管基底膜的增厚如何促进异常听觉功能。通过确定基底膜积累对周围听觉功能的后果来探索异常的地下室膜与听力损失之间的关系；评估对低氧相关的对基底膜积累的反应；通过抑制脊柱毛细管基底膜积累来改善缺氧和听觉功能障碍。提出了实验来检验两个假设的有效性：1）菌株组织中的异常地下膜导致耳蜗中代谢稳态的恶化，从而降低了耳蜗功能。通过用强烈但无损的声音刺激耗尽静电储量来检验该假设。暴露后，测量了血管的外围听觉函数以及血管的电化学和离子传输特性，以确定Stria和Scala培养基的稳态变化。 2）基底膜蛋白的积累上调与低氧相关的反应，该反应调节与基础膜稳态相关的基因。通过量化缺氧相关基因和蛋白质中蛋白质的表达来评估该假设。通过测量脊柱毛细管基底膜厚度，内凝切物电位和人耳塞氧张力来评估旨在逆转基底膜积累的药理操作。这些实验的结果提供了明确的描述，说明了地下膜异常在听觉功能障碍叙事中的作用：该项目评估了基底膜在内耳中的作用。该研究是在内耳的小鼠中进行的，其内耳的脊柱毛细血管基底膜增厚。该小鼠是基底膜异常的模型，因此获得的数据将与其他疾病状况相关，这些疾病状况增强了脊柱毛细血管基底膜和听力损失。