CORE--RESPIRATORY BIOLOGY AND INHALATION TOXICOLOGY

核心--呼吸生物学和吸入毒理学

• 批准号: 6577753
• 负责人: Joseph D Brain
• 金额: $ 22.85万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6577753
• 关键词: air pollution; asthma; bioassay; biological signal transduction; biomedical facility; cellular pathology; chronic bronchitis; cytokine; disease /disorder model; dogs; emphysema; environmental toxicology; laboratory mouse; laboratory rat; lung neoplasms; mitochondria; molecular cloning; occupational health /safety; pollutant interaction; pollution related respiratory disorder; pulmonary fibrosis /granuloma; respiratory disorder epidemiology; technology /technique development

Description: The Respiratory Biology and Inhalation Toxicology (RBIT) Core has as its objective "to understand how breathing results in environmental and occupational lung disease." The core seeks to develop prevention strategies and more effective treatments for pulmonary diseases including lung cancer, asthma, pulmonary fibrosis, and emphysema. The RBIT Core is primarily concerned with the effects of inhaled environmental toxicants on the mammalian pulmonary system. The Respiratory Biology and Inhalation Toxicology Core is involved with five primary lines of investigation. First, they have investigated the mechanisms of particle binding to alveolar macrophages and epithelial cell lines. Their data suggest that the macrophage scavenger receptor system is responsible for the binding of charged particles such as latex beads and titanium dioxide as well as quartz, fly ash and urban air particulates. This system did not appear to be operative in A549 epithelial cell lines. They now wish to pursue studies of the calcium concentration dependency of this binding and inhibition of this binding by scavenger receptor ligands. They have determined that appropriately-raised polyclonal antibodies block particle binding. Thus, they would like to investigate the molecular biology of this further using scavenger receptor knock out mice and expression cloning of blocking antibodies. Lastly , they plan to study the effects of mitochondrial oxidant production on cytokine release upon exposure to quartz versus titanium. The second line of investigation seeks to elucidate the mechanism of the epidemiologic finding that mortality of cardiovascular etiology is elevated about 24 hours after peaks in the concentration of urban air particulates (PM10). To carry out these studies they have used the ambient air particle concentrator (a series of virtual impactors) built by Sioutas and Koutrakis, et al. to generate concentrated urban air aerosols from Boston ambient air. Animal models (dogs, rats, and mice) are used that attempt to recreate the susceptibility factors that are associated with mortality during urban air inversions. Included are a chronic bronchitis model, various knock out mice, and dogs with induced cardiac ischemia. The third research interest concerns the physiology and biology of airway hyper-responsiveness. This group has worked extensively with a technique that measures the stiffness of smooth muscle cell cytoskeleton by manipulating and measuring the effects of cytoskeleton-bound ferromagnetic spheres on magnetic fields. This technique allows Respiratory Biology and Inhalation Toxicology Core investigators to test the effects of cytokines or pharmacologic agents on the contractility of airway smooth muscle cells. They are also interested in developing mouse models for allergic inflammation and airway hyper-responsiveness. They describe their fourth area of research interest as the development and application of bioassays for lung injury. For the most part this appears to be an effort to bring published assays into the laboratory s repertoire. Assays include lavage cytokines, enzymes, proteins, and message for several mediators. The last area of investigation described for the Respiratory Biology and Inhalation Toxicology Core is studies of the molecular mechanisms of pulmonary inflammation. In this work the investigators are considering signal transduction pathways for lung cell adhesion and the dynamics of neutrophil migration into the lung. They are also investigating the cells and chemokines that trigger the release of reactive oxygen species. In particular, they have studied rat MIP-1 alpha and MIP-2, a neutrophil chemotactic chemokine. Within these research studies is evidence of collaboration between the Respiratory Biology and Inhalation Toxicology Core and several other cores and facilities within the Center. Most notable are the Environmental Epidemiology Research Core and the Toxicology Research Core although there is reference to the Occupational Health Core and the Environmental Sciences and Engineering Core as well. The Respiratory Biology and Inhalation Toxicology Core investigators rely on a number of facilities for equipment and expertise. A central molecular biology laboratory provides nucleic acid and protein sequencing, PCR, in site hybridization and immunocytochemistry. Tissue and cell culture facilities are maintained within the Physiology Program. The Bioimaging Core provides laser scanning, confocal microscopy and morphometrics capabilities. The two electron microscopy laboratories offer scanning and transmission electron microscopy with electron specrtoscope imaging capabilities. An inhalation toxicology laboratory has three 1m3 Lucite chambers and two 100 l Lucite chambers. They are primarily set-up for the generation of gases (ozone and So2) and for concentrated Boston ambient air particles. The Respiratory Biology and Inhalation Toxicology Core is equipped with devices for blood and gaseous phase gas analysis and devices for respiratory mechanics and electrophysiology. Lastly, the core has developed a device for magnetometry in order to study changes in cytoskeletal stiffness.

描述：呼吸生物学和吸入毒理学(RBIT)核心 其目标是“了解呼吸如何在环境和环境中产生 职业性肺病。核心是寻求制定预防策略 以及对包括肺癌在内的肺部疾病更有效的治疗， 哮喘、肺纤维化和肺气肿。RBIT核心主要是 关注吸入环境毒物对哺乳动物的影响 肺部系统。 呼吸生物学和吸入毒理学核心涉及五项 调查的主要线索。首先，他们研究了 颗粒与肺泡巨噬细胞和上皮细胞系结合。他们的 数据表明，巨噬细胞清道夫受体系统负责 乳胶珠和二氧化钛等带电粒子的结合 以及石英、飞灰和城市空气颗粒物。但这个系统并没有 似乎在A549上皮细胞系中起作用。他们现在希望继续 这种结合和抑制的钙浓度依赖关系的研究 清道夫受体配体的这种结合。他们已经确定 适当提高的多克隆抗体可阻断颗粒结合。因此，他们 想要进一步研究这一现象的分子生物学 清道夫受体基因敲除小鼠及其阻断基因的表达克隆 抗体。最后，他们计划研究线粒体氧化剂的作用。 暴露于石英和钛时细胞因子释放的产生。 第二条调查线试图阐明 流行病学研究发现，心血管病因学死亡率上升 城市空气颗粒物浓度达到峰值后约24小时 (PM10)。为了进行这些研究，他们使用了环境空气颗粒物 由Sioutas和Koutrakis建造的集中器(一系列虚拟撞击器)， 等人的研究。从波士顿的环境空气中产生浓缩的城市气溶胶。 动物模型(狗、大鼠和小鼠)被用来试图重建 与城市空气中的死亡率相关的易感因素 反转。包括慢性支气管炎模型，各种基因敲除小鼠， 以及诱发心肌缺血的狗。 第三个研究兴趣涉及呼吸道的生理学和生物学。 反应过度。这个小组广泛地使用了一种技术 通过操纵和测量平滑肌细胞细胞骨架的硬度 细胞骨架结合的铁磁球对磁感应强度的影响 菲尔兹。这项技术允许呼吸生物学和吸入毒理学 核心调查人员将测试细胞因子或药理学药物对 呼吸道平滑肌细胞的收缩能力。他们还感兴趣的是 发展过敏性炎症和呼吸道高反应性的小鼠模型。 他们将他们的第四个研究领域描述为发展和 肺损伤生物检测方法的应用。在很大程度上，这似乎是 努力将已发表的化验结果带入实验室S的剧目。 检测包括灌洗液中的细胞因子、酶、蛋白质和几种 调解人。 最后描述的研究领域是呼吸生物学和 吸入性毒理学的核心是研究肺损伤的分子机制 发炎。在这项工作中，调查人员正在考虑信号 肺细胞黏附的转导途径与中性粒细胞的动力学 迁移到肺部。他们还在研究细胞和趋化因子。 这会引发活性氧物种的释放。特别是，他们有 研究了大鼠MIP-1α和中性粒细胞趋化趋化因子MIP-2。 在这些研究研究中，有证据表明 呼吸生物学和吸入毒理学核心和其他几个核心和 中心内的设施。最值得注意的是环境流行病学 研究核心和毒理学研究核心尽管有参考价值 职业健康核心与环境科学与工程 核心也是如此。 呼吸生物学和吸入毒理学核心研究人员依赖于 设备和专业知识设施的数量。一个中心分子生物学 实验室现场提供核酸和蛋白质测序，即聚合酶链式反应 杂交和免疫细胞化学。组织和细胞培养设施是 在生理学课程范围内维持。生物成像核心提供激光 扫描、共聚焦显微镜和形态测量功能。两个人 电子显微镜实验室提供扫描和传输电子 具有电子光谱成像能力的显微镜。一次吸气 毒理实验室有三个1m~3的绿帘子室和两个100立方米的L绿帘子室 钱伯斯。它们主要是用来产生气体(臭氧和 SO2)和浓缩的波士顿环境空气颗粒物。《呼吸》 生物和吸入毒理学核心配备了血液和吸入性设备 呼吸力学和气相气体分析及装置 电生理学。最后，该磁芯开发了一种磁测量装置 以研究细胞骨架硬度的变化。