RESPONSE IN LUNG EXTRACELLULAR MATRIX TO ASBESTOS

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 由于蒙大拿州利比居民接触到石棉污染的蛭石，对石棉相关疾病的关注再次出现。 蛭石分布在全国200多个地点，疾病发展潜伏期长，使石棉相关疾病成为一个持续的公共卫生问题。 先前的研究表明，Sparc和Adam 28在暴露于石棉的小鼠肺中的表达增加，包括暴露于Libby闪石的小鼠肺。 Sparc和Adam 28都编码参与细胞外基质（ECM）调节的蛋白质  细胞相互作用，包括类似于纤维化期间发生的组织重塑。这些蛋白质的功能使它们成为参与石棉暴露后发生的纤维化的令人兴奋的候选者。 我们的假设是，由Sparc和Adam 28编码的蛋白质的表达是石棉暴露后肺纤维化发展的重要步骤。 为了检验该假设，具体目标是：1）在暴露于盐水、Libby闪石和青石棉后，在Sparc缺失和匹配的野生型小鼠中建立Sparc和Adam 28的体内基因和蛋白表达，和2）通过检查ECM产生来确定从Sparc缺失和匹配的野生型小鼠分离的原代肺成纤维细胞培养物对相同三种处理的响应。 拟议的研究将加强理解细胞和ECM之间的相互作用，响应利比闪石。 由于成千上万的暴露个体面临健康风险，这些研究的最终目标是为这些和其他类似的肺部疾病确定新的治疗靶点。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Attention to asbestos-related diseases has re-emerged due to the exposure of Libby, Montana residents to asbestos-contaminated vermiculite. Vermiculite distribution to over 200 sites nationwide and the long latent period for disease development make asbestos-related diseases a continuing public health issue. Previous studies demonstrated increased expression of Sparc and Adam28 in asbestos-exposed mouse lungs, including those exposed to the Libby amphibole. Both Sparc and Adam 28 encode proteins involved in the regulation of extracellular matrix (ECM)  cell interactions, including the tissue remodeling similar to that occurring during fibrosis. The functions of these proteins make them exciting candidates for involvement in the fibrosis that occurs after asbestos exposure. Our hypothesis is that expression of the proteins encoded by Sparc and Adam28 are significant steps in the development of lung fibrosis after asbestos exposure. To test the hypothesis, the specific aims will 1) establish the in vivo gene and protein expression of Sparc and Adam28 in Sparc-null and matched wild-type mice after exposure to saline, the Libby amphibole, and crocidolite asbestos and 2) determine the response of primary lung fibroblast cultures isolated from the Sparc-null and matched wild-type mice to the same three treatments by examining ECM production. The proposed studies will enhance understanding of the interaction between cells and ECM in response to the Libby amphibole. With health risks faced by thousands of exposed individuals, the ultimate goal of these studies is to identify novel therapeutic targets for these and other similar lung diseases.