The role of SPARC in lung fibrosis

SPARC在肺纤维化中的作用

• 批准号: 8432592
• 负责人: Elizabeth A Putnam
• 金额: $ 42万
• 依托单位: UNIVERSITY OF MONTANA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-21 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8432592
• 关键词: Address; Amphibole Asbestos; Amphiboles; Asbestos; Asbestosis; Attention; Breathing; Candidate Disease Gene; Cell Communication; Cell Line; Cells; Chronic; Crocidolite Asbestos; Cysteine; Deposition; Development; Disease; Disease Progression; Elements; Environmental Exposure; Exposure to; Extracellular Matrix; Fiber; Fibroblasts; Fibrosis; Gene Expression; Goals; Growth Factor; Hamman-Rich syndrome; Health; Home environment; Human; Human Cell Line; In Vitro; Incidence; Individual; Inflammation; Investigation; Lung; Lung diseases; Maintenance; Malignant neoplasm of lung; Measures; Mesothelioma; Mining; Molecular; Montana; Mus; Pathway interactions; Patients; Play; Population; Process; Production; Proteins; Public Health; Pulmonary Fibrosis; RNA Interference; Regulation; Research Design; Rest; Risk; Role; Signal Transduction; Site; Testing; Time; United States; United States Environmental Protection Agency; Wild Type Mouse; improved; in vivo; lung development; mouse model; new therapeutic target; operation; protein expression; public health relevance; response; superfund site; vermiculite

DESCRIPTION (provided by applicant): National attention has been drawn to asbestos-related diseases (ARD) due to the serious health situation in Libby, Montana. For almost 60 years Libby miners and residents were exposed to asbestos- contaminated vermiculite from a mining operation near town. Both occupationally- and environmentally- exposed individuals have shown a much higher incidence of ARD than the rest of the population (ATSDR, 2003). However, exposure to the asbestos-contaminated vermiculite is not limited to Libby residents: distribution of this vermiculite nationwide and the long latent period for disease development make asbestos-related diseases (ARD) a continuing public health issue. We previously investigated gene expression changes in a mouse model of asbestos exposure and identified a candidate gene for study that we hypothesize plays a role in disease progression. SPARC (secreted protein acidic and rich in cysteine) demonstrates reproducibly increased expression in mouse lungs exposed to several types of asbestos fibers, including the Libby amphibole. SPARC is a matricellular protein involved in the regulation of extracellular matrix (ECM) - cell interactions through a hypothesized modulation of growth factor activity. The goal of this project is to delineate the role of SPARC in response to exposure to the Libby amphibole and crocidolite asbestos as a positive control. The hypothesis to be tested in our studies is that expression of SPARC is a significant step in the development of lung fibrosis after asbestos exposure. To test the hypothesis, the specific aims will 1) ssess the in vivo expression of SPARC and proteins in the TGF-¿ signaling cascade in SPARC-null and matched wild-type mice after induction of lung fibrosis through intratracheal asbestos instillation, and compare this with the effects of subsequent RNAi transduction to control SPARC expression in wild-type mice, and 2) establish the in vitro gene and protein expression of SPARC as well as extracellular matrix production in mouse primary lung fibroblasts and an immortalized human lung fibroblast cell line stimulated by TGF-¿ or amphiboles before and after Sparc expression inhibition by RNAi. The investigation proposed here will further determine the role of SPARC in fibrosis development after amphibole exposure, specifically targeting how inhibition of SPARC expression can regulate ECM production. Proteins involved in pathways regulated by SPARC could provide targets for potential therapies that might also be beneficial for the treatment of similar, non-asbestos caused diseases such as idiopathic pulmonary fibrosis.

描述（由适用提供）：由于蒙大拿州利比的严重健康状况，已经吸引了与石棉相关疾病（ARD）的全国关注。近60年来，利比矿工和居民在镇附近的一次采矿业务中暴露于石棉污染的vermicicelite中。偶然地和环境暴露的个体都表现出比其他人群更高的ARD事件（ATSDR，2003年）。但是，接触被石棉污染的ver虫不限于利比居民：在全国范围内的这种ver虫的分布和较长的潜在疾病发展时期，使石棉相关疾病（ARD）成为持续的公共卫生问题。我们先前研究了石棉暴露的小鼠模型中的基因表达变化，并确定了一个研究的候选基因，我们假设我们在疾病进展中起着作用。 SPARC（分泌的）蛋白质酸性和富含半胱氨酸的蛋白质）表现出在暴露于几种类型的石棉纤维（包括Libby闪比尔）的小鼠肺中可重复增加的表达。 SPARC是一种基质蛋白，参与了细胞外基质（ECM） - 通过假设的生长因子活性调节的细胞相互作用。该项目的目的是将SPARC的作用描述为暴露于Libby闪比尔和鳄鱼石棉的阳性。控制。在我们的研究中要检验的假设是，SPARC的表达是石棉暴露后肺纤维化发展的重要一步。为了检验假设，具体目的将1）在sparc-null中TGF- - 信号级联中的SPARC和蛋白质在体内表达，并在通过气管内石棉浸入肺中诱导肺纤维化后与野生型小鼠匹配，并将其比较。 随后的RNAi翻译以控制野生型小鼠中SPARC表达的影响，以及2）建立SPARC的体外基因和蛋白质表达以及小鼠原代肺成纤维细胞中的细胞外基质以及在以前和秋葵症中被TGF-Enction conction刺激的人肺成纤维细胞系中的肺成纤维细胞系中，或者是Sparc的表达。这里提出的投资将进一步确定SPARC在闪光暴露后纤维化发展中的作用，特别是针对SPARC表达的抑制如何调节ECM产生的作用。由SPARC调节的途径涉及的蛋白质可以为潜在疗法提供靶标，这些疗法可能也有益于治疗类似的非囊菌引起的疾病，例如特发性肺纤维化。