STRESS GENES AS BIOMARKERS OF MINERAL DUST EXPOSURE

应激基因作为矿尘暴露的生物标志物

• 批准号: 2277527
• 负责人: CYNTHIA R TIMBLIN
• 金额: $ 5.4万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-30 至 1997-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2277527
• 关键词: asbestos; biomarker; dust; gene expression; molecular pathology; occupational hazard; occupational stressor; oxidative stress; oxidizing agents; respiratory disorder; silicates; stress proteins; tissue /cell culture; transfection; asbestos; biomarker; dust; gene expression; molecular pathology; occupational hazard; occupational stressor; oxidative stress; oxidizing agents; respiratory disorder; silicates; stress proteins; tissue /cell culture; transfection

Occupational exposure to asbestos or silica is associated with the development of both non-malignant and malignant pulmonary disease. Considerable evidence indicates that the mechanism of mineral dust toxicity involves the production of active oxygen species (AOS) catalyzed directly on the mineral surface or by phagocytic cells within the lung. Production of AOS in excess of cellular defenses creates an environment of oxidative stress for the cell. The molecular response of cells to stress is a reprogramming of gene expression to meet the new challenges of its environment. Oxidant- induced genes include: genes encoding antioxidant enzymes, protooncogenes, hsp70, grp78, gadd45, and gad153. Detailed characterization of the molecular stress responses to asbestos or silica will aid in the understanding of the mechanisms of mineral dust mediated disease formation and may identify biomarkers of exposure and/or disease development. The focus of this proposal is to characterize the molecular stress response within target cells of asbestos or silica exposed lung, to compare this response to that elicited by other oxidants, and to related this response to known markers of disease in well-characterized inhalation models. The objectives of this grant are; 1) to evaluate in vitro and in vivo models of asbestos and silica exposure for changes in hsp70, grp78, gadd45, and gadd153 steady state mRNA; 2) to relate these changes in vitro to other oxidant stress inducing agents and 3) to modulate expression of c- jun in target cells using transfection techniques and to determine its role in mineral dust-mediated disease.

职业暴露于石棉或二氧化硅与 非恶性和恶性肺疾病的发展。 大量证据表明矿物粉尘毒性的机制 涉及直接催化活性氧（AOS）的产生 在矿物表面或通过肺部内的吞噬细胞。 生产 超过细胞防御的AO会产生一个氧化的环境 细胞的压力。 细胞对应激的分子反应是 重新编程基因表达以应对其新挑战 环境。 氧化剂诱导的基因包括：编码抗氧化剂的基因 酶，原子基因，HSP70，GRP78，GADD45和GAD153。 详细的 对石棉或二氧化硅的分子应力反应的表征 将有助于理解矿物灰尘介导的机制 疾病形成，可能识别出暴露和/或疾病的生物标志物 发展。 该提议的重点是表征分子 石棉或二氧化硅暴露于肺的靶细胞内的应力反应， 将此反应与其他氧化剂引起的反应和相关的反应进行比较 在特征良好的吸入中对已知疾病标记的这种反应 型号。 这笔赠款的目标是； 1）评估体外和 HSP70，GRP78的变化的石棉和二氧化硅暴露的体内模型 GADD45和GADD153稳态mRNA； 2）在体外关联这些变化 到其他氧化应激诱导剂和3）调节c-的表达 使用转染技术在目标细胞中的JUN并确定其作用 在矿物粉尘介导的疾病中。