MOLECULAR MECH. OF ASBESTOS & MESOTHELIAL CELL INTERACT.

拟议研究的长期目标是确定 石棉，一种公认的肺部病原体，其分子机制 在体外和体内与细胞相互作用以刺激释放 炎症和纤维化的介体。为此，两国之间的互动 青石棉和兔胸膜间皮细胞将被研究 作为石棉-细胞相互作用的范例。在最近的工作中，申请人 发现青石棉对兔胸膜间皮细胞的暴露 石棉体外诱导细胞因子白介素8(IL-8) 对中性粒细胞有很强的趋化活性。石棉与石棉的相互作用 调控IL-8或其他基因表达的细胞尚不清楚。石棉 纤维可能通过中介传递IL-8基因表达变化的信号 例如活性氧物种(由石棉产生)或蛋白质(由石棉产生 通过间皮细胞)，或通过与细胞的外部相互作用 环境(细胞外基质蛋白)或内部环境( 细胞骨架)。来检验石棉相互作用的假设 具有细胞外基质和细胞骨架的纤维是 石棉诱导基因表达及细胞外基质的影响 蛋白质和细胞骨架毒素对石棉诱导IL-8mRNA的影响 被分析。来检验石棉相互作用的假设 纤维和胸膜间皮细胞刺激间皮细胞 炎症和纤维化介质的产生，转化生长因子-β和 成员们将评估纤维连接蛋白蛋白的产生和mRNA的诱导 IL-8相关蛋白家族中的一组，以及一系列 将进行体内实验。 该奖项支持的工作不仅将提供关于 石棉致胸膜疾病的发病机制，但WIN也提供了 申请者拥有必要的工具来实现她成为一名 独立调查员。一项严格的培训计划已由 她的赞助商包括一系列的课程和会议。太空， 设施和受保护的研究时间已提供给 确立她的独立性。

The long-term objective of the proposed research is to determine the molecular mechanisms by which asbestos, a well recognized lung pathogen, interacts with cells in vitro and in vivo to stimulate the release of mediators of inflammation and fibrosis. To this end, the interaction of crocidolite asbestos and rabbit pleural mesothelial cells will be studied as a paradigm of asbestos-cell interactions. In recent work the applicant found that exposure of rabbit pleural mesothelial cells to crocidolite asbestos in vitro induced message for interleukin-8 (IL-8), a cytokine with potent chemotactic activity for neutrophils. How asbestos interacts with the cell to regulate IL-8 or other gene expression is not clear. Asbestos fibers may signal changes in IL-8 gene expression through intermediaries such as active oxygen species (produced by asbestos), or proteins (produced by mesothelial cells), or through interaction with the cells' external environment (extracellular matrix proteins), or internal environment (the cytoskeleton). To test the hypothesis that the interaction of asbestos fibers with the extracellular matrix and cytoskeleton is necessary for asbestos induced gene expression, the effect of extracellular matrix proteins and cytoskeletal toxins, on asbestos-induction of IL-8 MRNA will be analyzed. To test the hypothesis that the interaction of asbestos fibers and the pleural mesothelial cell stimulates the mesothelial production of mediators of inflammation and fibrosis, TGF-beta and fibronectin protein production and MRNA induction will be assessed, members of the family of IL-8 related proteins will be identified, and a series of in vivo experiments will be performed. The work supported by this award will not only yield information about the pathogenesis of asbestos-induced pleural disease, but win also provide the applicant with the tools necessary to achieve her goal of becoming an independent investigator. A rigorous training program has been planned by her sponsors including a series of courses and conferences. Space, facilities, and protected time for research have been made available to establish her independence.