Development of Biomarkers for Chronic Beryllium Disease in Mice

doi:10.2172/1060004

GSTDTAP > 地球科学

DOI	10.2172/1060004
报告编号	DE-FG02-08ER64670-1
来源ID	OSTI ID: 1060004
	Development of Biomarkers for Chronic Beryllium Disease in Mice
	Gordon, Terry
	2013-01-25
出版年	2013
语种	英语
国家	美国
领域	地球科学
英文摘要	Beryllium is a strategic metal, indispensable for national defense programs in aerospace, telecommunications, electronics, and weaponry. Exposure to beryllium is an extensively documented occupational hazard that causes irreversible, debilitating granulomatous lung disease in as much as 3 - 5% of exposed workers. Mechanistic research on beryllium exposure-disease relationships has been severely limited by a general lack of a sufficient CBD animal model. We have now developed and tested an animal model which can be used for dissecting dose-response relationships and pathogenic mechanisms and for testing new diagnostic and treatment paradigms. We have created 3 strains of transgenic mice in which the human antigen-presenting moiety, HLA-DP, was inserted into the mouse genome. Each mouse strain contains HLA-DPB1 alleles that confer different magnitude of risk for chronic beryllium disease (CBD): HLA-DPB10401 (odds ratio = 0.2), HLA-DPB10201 (odds ratio = 15), HLA-DPB11701 (odds ratio = 240). Our preliminary work has demonstrated that the 1701 allele, as predicted by human studies, results in the greatest degree of sensitization in a mouse ear swelling test. We have also completed dose-response experiments examining beryllium-induced lung granulomas and identified susceptible and resistant inbred strains of mice (without the human transgenes) as well as quantitative trait loci that may contain gene(s) that modify the immune response to beryllium. In this grant application, we propose to use the transgenic and normal inbred strains of mice to identify biomarkers for the progression of beryllium sensitization and CBD. To achieve this goal, we propose to compare the sensitivity and accuracy of the lymphocyte proliferation test (blood and bronchoalveolar lavage fluid) with the ELISPOT test in the three HLA-DP transgenic mice strains throughout a 6 month treatment with beryllium particles. Because of the availability of high-throughput proteomics, we will also identify changes in potential protein biomarkers in beryllium-treated mice. We will correlate these findings with the ability of the transgenic mice to develop a beryllium-specific adaptive immune response in blood and bronchoalveolar lavage (BAL) fluid. We will also determine whether beryllium-responsive CD4+ T cells in blood and BAL correlate with the onset of granuloma formation. Thus, we will provide the scientific community with biomarkers of sensitization and disease progression for CBD. These biomarkers will serve as critical tools for development of improved industrial hygiene and therapeutic interventions.
英文关键词	beryllium biomarkers
URL	查看原文
来源平台	US Department of Energy (DOE)
引用统计
文献类型	科技报告
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/6075
专题	地球科学
推荐引用方式 GB/T 7714	Gordon, Terry. Development of Biomarkers for Chronic Beryllium Disease in Mice,2013.