Protein kinase C and MAPK in epithelial responses

吸入的颗粒物如石棉会损害肺上皮细胞，进而引发代偿性增殖反应，最终导致纤维增生性肺病。在各种肺细胞类型中介导这一系列事件的细胞信号传导事件尚不完全清楚。然而，我们在动物和细胞培养模型中的初步数据表明，石棉诱导的蛋白激酶C（PKC）激活是石棉相关结果的早期事件。此外，石棉的某些影响，包括一些功能上与增殖，损伤和基因表达变化有关的影响，是PKC依赖的。蛋白激酶C（PKC）是一类具有选择性功能的丝氨酸/苏氨酸激酶家族。因此，我们建议确定哪些PKC亚型被石棉激活，哪些PKC亚型改变MAPKs和AP-1依赖基因表达的活性。这些研究将提供石棉介导的信号事件的机制信息。最后，我们建议产生的动物，基因改变，肺上皮细胞中的功能PKC δ减少。这些动物将用于吸入研究，以专门评价PKC δ在上皮细胞增殖和纤维增生性疾病中的作用。使用石棉作为模型，这些研究对单个PKC在其他类型的肺部病理中的作用也有更广泛的意义。

Inhaled particulates such as asbestos damage lung epithelial cells which in turn, triggers a compensatory proliferative response and ultimately fibroproliferative lung diseases. The cell signaling events that mediate this constellation of events in the various lung cell types are not fully known. However, our preliminary data in animal and cell culture models demonstrate that asbestos-induced activation of protein kinase C (PKC) is an early event in asbestos-associated outcomes. Furthermore, certain effects of asbestos, including some that are functionally related to proliferation, injury and changes in gene expression, are PKC-dependent. PKCs are a family of Ser/Thr kinases with selective functions. Thus, we propose to determine which PKC isoforms are activated by asbestos and which PKC isoforms modify activities of MAPKs and AP-1 dependent gene expression. These studies will provide mechanistic information on asbestos-mediated signaling events. Finally, we propose to generate animals that are genetically altered to have decreased functional PKCdelta in lung epithelial cells. These animals will be used in inhalation studies to specifically evaluate the role of PKCdelta in epithelial cell proliferation and fibroproliferative disease. Using asbestos as a model, these studies have broader implications for the role of individual PKCs in other types of lung pathologies as well.