RESPONSE IN LUNG EXTRACELLULAR MATRIX TO ASBESTOS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。由于蒙大拿州利比居民接触石棉污染的蛭石，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，在暴露于石棉的小鼠肺中，包括暴露于Libby角孔的小鼠肺中，Sparc和Adam28的表达增加。Sparc和adam28编码的蛋白质都参与细胞外基质（ECM）和细胞相互作用的调节，包括类似于纤维化过程中发生的组织重塑。这些蛋白的功能使它们成为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Adam28编码的蛋白的表达是石棉暴露后肺纤维化发展的重要步骤。为了验证这一假设，具体目标将是：1)在暴露于生理盐水、利比角孔和石棉后，在Sparc-null和匹配的野生型小鼠中建立Sparc和Adam28的体内基因和蛋白表达；2)通过检测ECM的产生，确定从Sparc-null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反应。拟议的研究将加强对细胞与ECM之间相互作用的理解，以响应Libby角闪孔。由于成千上万的暴露者面临着健康风险，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.