DYSREGULATED EXPRESSION OF SIGNALING MOLECULES IN ACUTE LUNG INJURY

急性肺损伤中信号分子的表达失调

• 批准号: 6110231
• 负责人: Guy A. Zimmerman
• 金额: $ 17.12万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-01 至 1999-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6110231
• 关键词: adult respiratory distress syndrome; biological signal transduction; cell cell interaction; chemokine; clinical research; cytokine; gene expression; genetic library; human subject; inflammation; laboratory mouse; leukocyte activation /transformation; molecular cloning; neutrophil; subtraction hybridization; tissue /cell culture; vascular endothelium

A fundamental hypothesis in our Special Center of Research is that dysregulated cell-cell interactions initiate and/or amplify inflammatory injury to the alveolar capillary membrane in Acute Respiratory Distress. Syndrome (ARDS), a common and lethal cause of lung damage, and that endothelial cells are critically involved. Identification of signaling molecules and other factors dysregulated cell-cell interactions in ARDS is a central and long-term goal of this project. In the current application, we focus on signaling molecules for neutrophils synthesized by stimulated and injured human endothelial cells. Neutrophils (PMNs) initiate, amplify, and influence the maintenance and outcome of acute lung injury. Endothelial cells are the first structural cells that PMNs encounter in the inflamed and injured lung and, by virtue of their ability to synthesize signaling molecules on a variety of classes, are particular points of dysregulated information transfer to the leukocytes. The mechanisms that regulate the expression and biologic actions of endothelial signaling molecules of the same or different classes, the identities of some of these signaling factors, and the mechanisms by which they become dysregulated in inflammatory injury are largely unknown. This project addresses each of these issues in interrelated studies based on the above hypotheses and on observations and preliminary data generated in the current funding period. The first specific aim is to characterize the regulation of expression and actions of chemokines produced by human endothelial cells that signal neutrophil activation, focusing on ENA-78 and related family members. The second specific aim is to characterize new endothelial signaling factors that we have identified by screening cDNA libraries from stimulated endothelial cells and by subtractive hybridization. The third specific aim is to characterize expression and distribution of endothelial signaling molecules in lung tissue from patients with ARDS and in tissue from control and comparative subjects. The fundamental and correlative nature of these studies will yield new knowledge that may lead to novel strategies of prevention and therapy of ARDS.

我们特殊研究中心的一个基本假设是 调节失调的细胞间相互作用引发和/或放大炎症 急性呼吸窘迫对肺泡毛细血管膜的损伤 综合征(ARDS)，一种常见的致命的肺损伤原因， 血管内皮细胞受到了严重影响。信令识别 ARDS中的分子和其他因素调节细胞间的相互作用 这是该项目的一个核心和长期目标。在本申请中， 我们专注于通过刺激合成的中性粒细胞的信号分子。 和损伤的人内皮细胞。中性粒细胞(PMN)启动、放大、 并影响急性肺损伤的维持和转归。 内皮细胞是中性粒细胞首先遇到的结构细胞。 发炎和受伤的肺部，凭借它们的能力 合成各种类别的信号分子，都是特别的 调节失调的信息传递到白细胞的点。这个 调控基因表达和生物学行为的机制 相同或不同类别的内皮信号分子， 其中一些信号因子的身份，以及通过什么机制 它们在炎症性损伤中变得失调在很大程度上是未知的。这 该项目在相互关联的研究中解决了这些问题中的每一个， 上述假设以及在#年产生的观测和初步数据 目前的资助期。 第一个具体目标是描述表达的调节和 人内皮细胞产生的趋化因子在信号传导中的作用 中性粒细胞激活，主要是ENA-78和相关家族成员。 第二个具体目标是表征新的内皮信号 我们通过筛选cDNA文库确定的因素 刺激内皮细胞和消减杂交法。 第三个具体目标是表征表达和分布 ARDS和ARDS患者肺组织内皮细胞信号分子的表达 在对照和比较对象的组织中。 这些研究的基础性和关联性将产生新的 可能导致新的预防和治疗策略的知识 阿兹。