PROTECTIVE ROLE OF APOPTOSIS IN ASBESTOS PLEURAL INJURY

描述：胸膜间皮细胞，胸膜间皮细胞的前体 石棉诱导的肿瘤间皮瘤，暴露于 石棉。重要的机制可能包括氧自由基的产生，DNA 损伤和纤维内化。因为无法进行细胞凋亡 可能会让DNA受损的细胞存活下来，而细胞凋亡的丧失可能是 在导致肿瘤的多步骤过程中的主要步骤。因此， 促进或抑制细胞凋亡的机制可能是一个动态过程 确定石棉的毒性效应最终是否会导致 肿瘤。我们建议研究细胞凋亡在病理学中的作用。 石棉对间皮细胞和胸膜的影响。最初，布罗德杜斯博士 旨在阐明石棉诱导细胞凋亡的主要机制。 兔和人胸膜间皮细胞及兔胸膜。通过 DNA损伤、氧化应激和应激相关信号的测量 (神经酰胺，Jun激酶，MAP激酶)在体外和体内，她建议展示 间皮细胞凋亡的重要途径。然后，她会决定 某些信号，也就是那些由 Vitronectin受体，抑制石棉诱导的细胞凋亡。vbl.使用 玻璃连接素包被的颗粒或抗整合素抗体激活 整合素，她将确认Vitronectin受体的作用是 抗细胞凋亡，并确定整合素是否改变了平衡 神经酰胺和JNK等细胞凋亡途径与增殖的关系 MAP激酶等通路。激活后在兔体内的研究 或抑制Vitronectin受体或基因工程小鼠 没有了Vitronectin或Vitronectin受体，她就会明白 在体内的这种抗细胞凋亡的作用。最后，她打算使用 石棉诱导细胞凋亡的抑制剂(抗氧化剂B-胡萝卜素， 抑制PARP，玻璃连结素包被的珠子)，以确定长期 抑制细胞凋亡将导致DNA损伤的积累 暴露于石棉的间皮细胞。我们将长期评估 石棉暴露细胞DNA结构损伤的存在 微核的存在和基因拷贝数的变化 比较基因组杂交。从这些研究中，布罗杜斯博士将 在没有转基因小鼠的情况下继续进行长期研究 Vitronectin，一种主要的Vitronectin受体的B5亚单位，或P53到 确认这种对细胞凋亡的抑制会导致敏感性增加 石棉引起的异常，包括间皮瘤。这些研究 应提供有关石棉的作用机理的重要信息 石棉对间皮细胞的诱导凋亡及作用 石棉诱导的病理中的细胞凋亡。

DESCRIPTION: Pleural mesothelial cells, the progenitor of the asbestos-induced tumor mesothelioma, undergo apoptosis when exposed to asbestos. Important mechanisms may include oxygen radical generation, DNA damage and fiber internalization. Because an inability to undergo apoptosis may allow cells with DNA damage to survive, a loss of apoptosis may be a major step in the multistep process leading to neoplasia. Therefore, mechanisms promoting or inhibiting apoptosis may play a dynamic process determining whether the toxic effects of asbestos eventually result in neoplasia. We propose to investigate the role of apoptosis in the pathology of asbestos to the mesothelial cells and pleura. Initially, Dr. Broaddus aims to delineate the major mechanisms inducing asbestos-induced apoptosis in both rabbit and human pleural mesothelial cells and rabbit pleura. By measures of DNA damage, oxidant stress and stress-related signaling (ceramide, jun kinase, MAP kinase) in vitro and in vivo, she propose to show the pathways essential to mesothelial apoptosis. Then, she will determine the mechanisms by which certain signals, namely those initiated by vitronectin receptors, inhibit asbestos-induced apoptosis. Using vitronectin-coated particles or anti-integrin antibodies to activate the integrins, she will confirm the role of vitronectin receptors as anti-apoptotic, and identify whether the integrins are altering the balance of the apoptotic pathways such as ceramide and JNK with proliferative pathways such as MAP kinase. In in vivo studies in rabbits after activation or inhibition of vitronectin receptors or in genetically-engineered mice without vitronectin or vitronectin receptors, she will learn the importance of this anti-apoptotic effect in vivo. Finally, she intends to use inhibitors of asbestos-induced apoptosis (anti-oxidant B-carotene, inhibition of PARP, vitronectin-coated beads) to determine whether longterm inhibition of apoptosis will lead to accumulation of DNA damage in asbestos-exposed mesothelial cells. We will assess chronically asbestos-exposed cells for the presence of DNA structural damage by the presence of micronuclei and for changes in gene copy number using comparative genomic hybridization. From these studies, Dr. Broaddus will proceed to long term studies in genetically-engineered mice without vitronectin, the B5 subunit of a major vitronectin receptor, or p53 to confirm that this inhibition of apoptosis leads to an increased sensitivity to asbestos-induced abnormalities, including mesothelioma. These studies should provide important information about the mechanisms by which asbestos induces apoptosis in mesothelial cells and the role of asbestos-induced apoptosis in asbestos-induced pathology.