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“了解呼吸如何影响环境和 职业性肺病。”核心旨在制定预防策略 以及针对包括肺癌在内的肺部疾病的更有效的治疗方法， 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 肺系统。 呼吸生物学和吸入毒理学核心涉及五个 主要调查线。首先，他们研究了机制 颗粒与肺泡巨噬细胞和上皮细胞系的结合。他们的 数据表明巨噬细胞清道夫受体系统负责 带电粒子（例如乳胶珠和二氧化钛）的结合 以及石英、飞灰和城市空气颗粒物。这个系统没有 似乎在 A549 上皮细胞系中起作用。他们现在想要追求 这种结合和抑制的钙浓度依赖性的研究 清道夫受体配体的这种结合。他们已经确定 适当培养的多克隆抗体可阻断颗粒结合。因此，他们 想进一步研究其分子生物学 清道夫受体敲除小鼠及阻断表达克隆 抗体。最后，他们计划研究线粒体氧化剂的影响。 暴露于石英与钛时细胞因子释放的产生。 第二条研究路线旨在阐明这一机制 流行病学发现心血管病因死亡率升高 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 由 Sioutas 和 Koutrakis 建造的集中器（一系列虚拟冲击器）， 等人。从波士顿环境空气中产生浓缩的城市空气气溶胶。 使用动物模型（狗、大鼠和小鼠）试图重现 与城市空气中死亡率相关的易感因素 倒置。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气道的生理学和生物学 过度反应。该小组广泛使用了一种技术 通过操纵和测量平滑肌细胞细胞骨架的硬度 测量细胞骨架结合的铁磁球对磁性的影响 字段。该技术允许呼吸生物学和吸入毒理学 核心研究人员测试细胞因子或药物对 气道平滑肌细胞的收缩性。他们还感兴趣 开发过敏性炎症和气道高反应性的小鼠模型。 他们将他们的第四个研究兴趣领域描述为开发和 生物测定在肺损伤中的应用在大多数情况下，这似乎是 努力将已发表的检测纳入实验室的库中。 检测包括灌洗细胞因子、酶、蛋白质和多种信息 调解员。 呼吸生物学描述的最后一个研究领域 吸入毒理学核心是研究肺部的分子机制 炎。在这项工作中，研究人员正在考虑信号 肺细胞粘附和中性粒细胞动力学的转导途径 迁移至肺部。他们还在研究细胞和趋化因子 触发活性氧的释放。特别是，他们有 研究了大鼠 MIP-1 α 和 MIP-2（一种中性粒细胞趋化因子）。 在这些研究中，有证据表明 呼吸生物学和吸入毒理学核心以及其他几个核心和 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 职业健康核心和环境科学与工程 核心也一样。 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。分子生物学的中心 实验室提供核酸和蛋白质测序、PCR、现场 杂交和免疫细胞化学。组织和细胞培养设施是 在生理学计划内维护。生物成像核心提供激光 扫描、共焦显微镜和形态测量功能。两人 电子显微镜实验室提供扫描和透射电子 具有电子能谱成像功能的显微镜。一次吸气 毒理学实验室拥有三个 1m3 有机玻璃室和两个 100 升有机玻璃室 室。它们主要用于产生气体（臭氧和 So2) 和波士顿环境空气中的浓缩颗粒。呼吸系统 生物和吸入毒理学核心配备了血液和吸入装置 用于呼吸力学的气相气体分析和装置 电生理学。最后，核心开发了磁力测量装置 以研究细胞骨架硬度的变化。