RESPONSE IN LUNG EXTRACELLULAR MATRIX TO ASBESTOS

该子项目是利用 NIH/NCRR 资助的中心拨款提供的资源的众多研究子项目之一。子项目和研究者 (PI) 可能已从另一个 NIH 来源获得主要资金，因此可以在其他 CRISP 条目中出现。列出的机构是中心的机构，不一定是研究者的机构。由于蒙大拿州利比居民接触受石棉污染的蛭石，人们重新开始关注与石棉相关的疾病。蛭石遍布全国 200 多个地点，疾病发展潜伏期长，使得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，暴露于石棉的小鼠肺部（包括暴露于利比角闪石的小鼠肺部）中 Sparc 和 Adam28 的表达增加。 Sparc 和 Adam 28 都编码参与细胞外基质 (ECM) 和细胞相互作用调节的蛋白质，包括类似于纤维化过程中发生的组织重塑。这些蛋白质的功能使它们成为参与石棉接触后发生的纤维化的令人兴奋的候选者。我们的假设是，Sparc 和 Adam28 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。为了检验这一假设，具体目标是 1) 在暴露于盐水、Libby 角闪石和青石棉后，在 Sparc-null 和匹配的野生型小鼠中确定 Sparc 和 Adam28 的体内基因和蛋白表达，2) 通过检查 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治疗的反应。拟议的研究将增强对细胞和 ECM 之间相互作用的理解，以响应利比角闪石。由于成千上万的暴露者面临健康风险，这些研究的最终目标是确定这些和其他类似肺部疾病的新治疗靶点。

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.