MECHANISMS OF TISSUE DESTRUCTION IN THE MIDDLE EAR

病理性骨重建(破骨细胞和成骨细胞活动耦合) 是慢性中耳炎听力损失的主要原因， 无胆脂瘤和耳硬化症的活动性病变。这 建议旨在了解这些机制 用来控制中耳的这些局部重塑过程 预防和逆转听力损失的远期目标 这些疾病造成的。破骨细胞活性在这些疾病中的调控 没有得到彻底的调查。在中耳疾病中，局部的 刺激信号必须激活自分泌或旁分泌因子 激活细胞活动，导致该部位的破骨细胞吸收。 此外，有证据表明这些本地化进程在 中耳可能会导致耳蜗性损伤。这项建议的目的是： 1.导致局限性骨丢失的细胞和生化事件。 软骨内和膜内骨将进行USCG光检查 光镜、透射电子显微镜和免疫组织化学 我们的加压中耳局部诱导骨吸收模型 沙鼠的生活。对导致局限性骨的因素的认识 损失对于制定合理的干预措施治疗糖尿病非常重要。 病理性骨重塑引起的中耳疾患。 2.由于局部因子(S)可能存在于骨骼区域 重塑，培养基会被注入到 加压中耳内的骨改建区域。这个 将对条件培养液的存在因素进行评估 可激活破骨细胞或吸引单核细胞。(初级文化 破骨细胞样细胞和单核细胞Boyden盲井小室 将被使用。)如果一个因子能被提取出来，它就会在以后被提纯。 并以此为特征。这些方法也可能会减少对 关于谎言动物和更多使用细胞培养。 3.导致局限性骨吸收的因素(S)的确切性质 以及改建都是未知数。在他的许多潜在的候选人中，他 因子是花生四烯酸的代谢物(前列腺素和 白三烯)。花生四烯酸代谢物及其抑制剂将是 在体内测试它们对抗破骨活性的活性，并 抗分离的破骨细胞样细胞。组织形态计量学与时间推移 将使用摄影技术。 4.具有活跃骨骼的动物会发生耳蜗毛细胞丢失 发生在中耳内的吸收。耳蜗性损伤(对头发) 细胞、神经纤维和血管纹)将在以下领域进行研究 邻近局限性的骨丢失和重塑。长期目标 这项研究的目的是确定在重塑过程中产生的因素 这个过程对内耳是有毒的。如果存在这样的因素，他们的 身份识别可以防止由于以下原因造成的耳蜗性听力损失 胆脂瘤和慢性中耳炎。

Pathological bone remodeling (coupled osteoclast and osteoblast activity) is a major cause of hearing loss in chronic otitis media, with and without cholesteatoma and in active lesions of otosclerosis. This proposal is directed toward an understanding of the mechanisms controlling these localized remodeling processes in the middle ear with the long range goal of preventing and reversing the hearing loss caused by these diseases. The control of osteoclast activity in these diseases has not been thoroughly investigated. In middle ear disease, local stimulatory signals must activate autocrine or paracrine factors which activate cellular events leading to osteoclastic resorption at that site. Furthermore, there is evidence that these localized processes within the middle ear may lead to cochlear damage. Aims of this proposal are: 1. Cellular and biochemical events leading to localized bone loss. Endochondral and intramembranous bone will be investigated uscg light microscopy, transmission electron microscopy and immunohistochemistry in our model of locally induced bone resorption in the pressurized middle ear of the gerbil. An understanding of factors leading to localized bone loss is important to develop rational interventions in the treatment of middle ear disorders caused by pathological bone remodeling. 2. Since is likely that local factor(s) are present in regions of bone remodeling, culture medium will be conditioned by infusing it into regions of bone remodeling within the pressurized middle ear. The conditioned medium will ben be evaluated for the presence of factors which may activate osteoclasts or attract monocytes. (Primary cultures of osteoclast-like cells and Boyden blind well chambers with monocytes will be used.) If a factor can be extracted, it will later be purified and characterized. These methods may also lead to less of a dependence on lie animals and a greater use of cell cultures. 3. The exact nature of factor(s) leading to localized bone resorption and remodeling are unknown. Of he many potential candidates for such a factor are the arachidonic acid metabolites (prostaglandins and leukotrines). Arachidonic acid metabolites and their inhibitors will be tested for their activity against osteoclastic activity in vivo and against isolated osteoclast-like cells. Histomorphometry and time-lapse cinematography will be used. 4. Cochlear hair cell loss occurs in animals which have active bone resorption occurring within the middle ear. Cochlear damage (to hair cells, nerve fibers and the stria vascularis) will be studied in areas adjacent to localized bone loss and remodeling. The long-term objective of this study is to determine if factors produced in the remodeling process are toxic to the inner ear. If such factors exist, their identification may allow the prevention of cochlear hearing loss due to cholesteatoma and chronic otitis.