NORA Manufacturing Sector Strategic Goals
9270036 - Mineral Dust-Induced Gene (MDIG) & Occupational Lung DiseaseStart Date: 10/1/2004
End Date: 9/30/2009
Principal Investigator (PI)Name: Fei Chen
Funded By: NIOSH
Primary Goal Addressed5.0
Secondary Goal Addressed6.0
Attributed to Manufacturing
The purpose of this project is to understand how the mineral dust-induced gene (mdig) is regulated upon exposure to inhaled particles and the role of induction of mdig in pulmonary disease. The hypothesis is that induction of the mdig gene is critically involved in silica-induced fibrosis and/or cancer, and, therefore, addresses Respiratory Disease and Cancer issues for working in the manufacturing and mining sector. This project will employ molecular-biology techniques to enhance our understanding of occupational lung diseases by defining the transcriptional regulation and function of this novel gene. In addition to elucidation of mechanisms of pathogenesis, the results obtained may lead to the development of useful biomarker for early detection or treatment of mineral dust-induced lung diseases in humans.
Our long-term goal is to understand how the mineral dust-induced gene (mdig) is regulated in health and various human disease states, especially mineral dust-induced lung disease. The objective of this application is to investigate transcriptional control of the gene that encodes the MDIG protein that is potentially involved in occupational mineral dust-induced fibrogenic and/or tumorigenetic lung diseases. The central hypothesis to be tested is that constitutive and stimulated transcription of mdig are mediated by trans-acting transcription factors that interact with cis-acting response elements in the promoter or 5'-flanking DNA region of the mdig gene. The rationale behind the research is that modulation of mdig gene expression may be one means of directly affecting lung cell proliferation and cell cycle transition in response to occupational exposure to mineral dusts, such as silica and asbestos. Three specific aims will be pursued: (1) identify DNA segments that most likely regulate constitutive and inducible transcription of the human mdig gene; (2) define DNA response elements and transcription factors that regulate constitutive and inducible transcription of the mdig gene; (3) determine the function of MDIG in cell growth and cell cycle regulation.
By the use of cellular models, several conventional and up-to-date molecular biology techniques will be used to achieve the goals of this project. These techniques include cell transfection, reporter gene activity assay, in vivo genomic footprinting, electrophoretic mobility shift assay, chromatin immunoprecipitation, RNA interference (RNAi), and DNA microarray.
At the completion of this research, we expect to have determined how transcription of the mdig gene is regulated, both constitutively and when stimulated by mineral dusts. We additionally expect, based on preliminary studies, that stimulated, and possibly, constitutive transcription of the mdig gene will be in part dependent upon the activation of nuclear factor-?B. Research to Practice (r2p) is an important component of this project. The significance of this project is, in addition to contributing to understanding normal physiologic and host defensive processes in response to the inhalation of mineral dusts, the results obtained from this project can potentially serve as a new biomarker for lung diseases induced by mineral dusts. In addition, the mechanistic data obtained should be of use in refinement of risk assessment efforts by OSHA in the upcoming rulemaking activity for silica.
At the completion of this project, researchers expect to have determined how transcription of mdig gene is regulated, both constitutively and when stimulated by mineral dusts. Additionally researchers expect, based on preliminary studies, that stimulated, and possibly, constitutive transcription of the mdig gene will be in part dependent upon the activation of NF-?B and c-Myc. Results of this study will enhance the understanding of normal physiologic and host defensive processes in response to the inhalation of mineral dusts, During the supporting period of this project, researchers also assume that three to five papers will be published in "main stream" scientific journals, such as Cancer Research, Journal of Biological Chemistry, Journal of Clinical Investigation, American Journal of Pathology, and Molecular and Cellular Biology. In addition, data will be presented at annual meetings. Project success will be judged by achievement of specific project aims, the quality and productivity of the project as judged by the number of publication in well-respected journals, and the impact in developing a biomarker for early detection of pulmonary mineral dust-induced disease.
Occupational dust-induced lung diseases, in particular asbestosis and silicosis, both of which are potentially linked to a large proportion of occupational lung cancer, will continue to produce a significant drain on human health and government resources in the future, not only because of the progressive nature of diseases (asbestosis and silicosis continue to develop even after exposure ceases), but also because of an apparent failure to comply with the permissible or recommended exposure limits in some working environments. For example, asbestosis deaths increased from fewer than 100 in 1968 to 1259 in 1999 and 1486 in 2000. In addition, significantly elevated mortality from silicosis was noted in miscellaneous non-metallic mineral and stone production, iron and steel foundries, and structural clay products industries. While it is crucial to continue the development and implementation of primary prevention strategies (reduction of airborne dust levels, personal barrier devices, etc.), these disturbing figures indicate that a significant number of workers who are currently exposed to mineral dusts are at risk for debilitating lung disease. However, the effects of various dust levels on biological systems are still unclear. Thus, the etiology and molecular mechanisms of disease processes, which result from the interaction of dust particles with cellular components of the lung, clearly deserve additional careful and concerted investigation. Elucidation of mechanisms of disease initiation and progression should assist in identification of biomarkers of disease and assist in risk assessment. The aim of this project is to identify an early marker of biological response and to elucidate mechanisms involved in initiation and progression of mineral dust-induced pulmonary fibrosis and lung cancer. Research to Practice (r2p) is an important component of this project. The results can potentially serve as a new biomarker for lung diseases induced by mineral dusts. In addition, the mechanistic data obtained should be of use in refinement of risk assessment efforts by OSHA in the upcoming rulemaking activity for silica.
Specific surveillance information used was NIOSH publication No. 2003-11, The Work-Related Lung Disease (World) Surveillance Report, 2002 and the information from MMWR.
This project supports the following goals:
Manufacturing Sector (50%), Goal 6: Reduce the prevalence of cancer due to exposure in the manufacturing sector.
Mining Sector (50%), Goal 1: Reduce respiratory diseases in miners by reducing health hazards in the workplace associated with coal worker pneumoconiosis, silicosis, and diesel emissions. Intermediate Goal 1.3 (09PPMINIG1.3) "Reduce coal miner exposure to silica and coal dust" and Intermediate Goal 1.4 (09PPMINIG1.4) "Reduce the silica exposure of workers in metal and non-metal mines and mills".
Cancer, Reproductive, Cardiovascular Diseases Cross Sector (50%), Goal 1: Reduce the incidence of work-related cancer. Intermediate Goal 1.1 (09PPCRCIG1.1) "Conduct research to reduce work-related cancer" Activity/Output Goal 1.1.3 (09PPCRCAOG1.1.3) "Develop and evaluate biomonitoring methods for the determination of carcinogen exposure and health effects in workers". Activity/Output Goal 1.1.6. (09PPCRCAOG1.1.6); "Assess how cancer risk is influenced by the interaction of human genetic variation with modifiable risk factors."
Respiratory Diseases Cross Sector (50%), Goal 4: Prevent and reduce work-related respiratory malignancies. Intermediate Goal 1.4 (09PPRDIG1.4) "Reduce the incidence of work-related cancer through research". Activity/Output Goal 4.1.4 (09PPRDRAOG4.1.4) "Elucidate mechanisms of silica-induced lung cancer".
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