RESPONSE IN LUNG EXTRACELLULAR MATRIX TO ASBESTOS

点击翻译按钮获取中文摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Attention to asbestos-related diseases (ARD) has intensified due to the exposure of Libby, MT residents to asbestos-contaminated vermiculite. Vermiculite distribution to 200+ sites nationwide and the long latent period for disease development make ARD a continuing public health issue. Exposures to asbestos fibers by inhalation cause multiple ARD including asbestosis, lung cancer and mesothelioma. This investigation will focus on asbestos-caused fibrosis by studying the role of SPARC in this process, since we found increased expression of SPARC in mouse lungs exposed to several types of asbestos fibers. SPARC is a matricellular protein involved in the regulation of extracellular matrix (ECM)cell interactions through modulation of growth factor activity. These previously identified functions make SPARC an exciting candidate for involvement in asbestosis. The investigations proposed here will elucidate the role of SPARC in asbestosis, specifically targeting how inhibition of SPARC expression can regulate ECM production. The goals of this project are to delineate the involvement of the matricellular protein SPARC in the regulation of ECM deposition in response to crocidolite and the Libby amphibole. The central hypothesis to be tested in our studies is that expression of SPARC is a significant step in the development of lung fibrosis through the modulation of ECM production. To test the hypothesis, we propose the following aims: 1) Establish the in vivo expression of SPARC and ECM proteins in Sparc-null and matched wild-type (WT) mice after exposure to saline, the Libby amphibole, and crocidolite asbestos. Key elements of this aim include the use of Sparc-null mice constitutively lacking the protein as well as RNA interference (RNAi) as a mechanism to control SPARC expression in WT mice after fiber exposure. 2) Characterize the response of primary lung fibroblast cultures isolated from Sparc-null and matched WT mice to saline, the Libby amphibole, and crocidolite asbestos. Key elements of this aim include analysis of ECM proteins as well as changes in gene expression after amphibole exposure. As a result of the proposed studies, we hope to achieve a better understanding of the role of SPARC in the development of lung fibrosis as measured by ECM production after amphibole exposure. We will also study the potential for blocking SPARC expression as a therapeutic measure to reduce the fibrotic response. By investigating a critical question concerning fibrosis development, this proposal will also begin to address the potential for using RNA interference to control SPARC expression as a treatment for fibrotic diseases of the lung. Because of the health risks faced by thousands of asbestos-exposed individuals, the ultimate goal of these studies is to identify a direction for the development of novel therapeutic targets for these and other similar environmentally-caused lung diseases. In addition, this potential therapy has implications for treatment of all forms of fibrosis, including IPF.