Molecular Basis of Otopathology

描述(申请人提供)：拟议调查的目标是更好地了解耳硬化症的分子病理学，并最终开发出更好的治疗和预防形式。其具体目的是研究正常小鼠和导致人类耳硬化症的遗传缺陷小鼠耳囊的骨代谢。我们将应用我们从小鼠模型中学到的东西，以更好地理解可能导致人类耳囊异常重塑的因素。为此，我们将从正常患者和耳硬化症患者获取骨标本，并研究成骨细胞骨细胞的培养。我们将把我们从小鼠研究中学到的东西应用到正常的人类耳囊生理学中，并确定哪些分子因素在启动耳囊重塑中起重要作用。具体地说，我们将研究I型胶原基因表达的缺陷，并确定这些缺陷对成骨细胞生理的影响，可能导致耳硬化症的发展。如果成功，这项拟议的研究将使人们更好地了解耳硬化症发生的分子因素，开发基因测试，以便识别有患耳硬化症风险的个人，以及评估潜在治疗药物的体外方法。

DESCRIPTION (provided by applicant): The goal of the proposed investigation is to achieve a better understanding of the molecular pathology of otosclerosis and ultimately develop better forms of treatment and prevention. The specific aims are to investigate bone metabolism of the otic capsule of normal mice and mice with genetic defects which give rise to otosclerosis in humans. We will apply what we learn from the mouse model to achieve a better understanding of factors which may result in abnormal otic capsule remodeling in humans. To accomplish this we will obtain bone specimens from normal patients and patients with otosclerosis, and study osteoblast bone cells in culture. We will apply what we learn from the mouse studies to normal human otic capsule physiology and determine which molecular factors are important in the initiation of otic capsule remodeling. Specifically, we will study defects in type 1 collagen gene expression and determine what effects these defects have on osteoblast physiology that may lead to the development of otosclerosis. If successful, the proposed study will result in a better understanding of the molecular factors involved in the development of otosclerosis, the development of genetic tests that will allow for identification of individuals who are at risk for developing otosclerosis, and an in vitro method for evaluating potential therapeutic agents.