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: 6302256
• 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: 1999
• 资助国家: 美国
• 起止时间: 1999-12-01 至 2000-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6302256
• 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.

我们特别研究中心的一个基本假设是， 失调的细胞-细胞相互作用引发和/或放大炎性 急性呼吸窘迫对肺泡毛细血管膜的损伤。 急性呼吸窘迫综合征（ARDS），肺损伤的常见和致命的原因， 内皮细胞是关键性的。信令识别 分子和其他因子在ARDS中失调的细胞-细胞相互作用， 这是该项目的长期目标。在当前应用中， 我们专注于中性粒细胞的信号分子， 和受损的人内皮细胞。中性粒细胞（PMN）启动，扩增， 并影响急性肺损伤的维持和转归。 内皮细胞是中性粒细胞在血管中遇到的第一个结构细胞。 发炎和受伤的肺，凭借他们的能力， 合成各种类别的信号分子，特别是 失调的信息传递到白细胞的点。的 调节表达和生物学作用的机制 相同或不同类别的内皮信号分子， 这些信号传导因子的身份，以及 它们在炎性损伤中变得失调在很大程度上是未知的。这 项目在相互关联的研究中解决了这些问题， 上述假设和观察结果以及 目前的融资期。 第一个具体目标是表征表达的调节， 人内皮细胞产生的趋化因子的作用， 中性粒细胞活化，重点是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传导 我们已经通过筛选cDNA文库， 刺激的内皮细胞和通过消减杂交。 第三个具体目标是表征表达和分布， ARDS患者肺组织中的内皮信号分子， 在来自对照和比较受试者的组织中。 这些研究的基本和相关性质将产生新的 知识，可能导致新的战略，预防和治疗 ARDS。