MECHANISM OF RSV INDUCED IL-8 GENE TRANSCRIPTION

描述 （摘自申请人摘要）研究的长期目标 提出，是为了了解呼吸道合胞病毒的机制， (RSV)诱导白细胞介素-8（IL-8）的表达，因为它与核 因子激活 儿童RSV感染导致9万人住院 在美国，每年有4500人入院和4500人死亡。 RSV诱导的炎症和损伤的机制尚不清楚，但似乎 涉及强烈的炎症反应。 IL-8，一种有效的趋化性和 白细胞活化剂，在RSV期间以增加的量产生 体外和体内气道细胞感染。 初步研究 表明NF-κ-B活化对于RSV诱导IL-8基因是关键的 表情 这项资助的工作假设指出，RSV蛋白质 激活NF-κ-B和其他核转录因子， 在气道细胞中协同诱导IL-8基因转录。 为了 为了验证这一假设，提出了以下具体目标：1） 鉴定所述细胞的5 '侧翼区中的顺式活性调节元件， IL-8基因，其响应RSV感染，2.）定义的作用 RSV病毒复制诱导IL-8基因转录和核因子 激活，3.）确定NF-κ-B酪氨酸磷酸化的作用 RSV中的亚基诱导NF-κ-B活化和IL-8基因表达，和4.） 确定单个RSV基因产物在刺激IL-8基因中的作用 转录通过核因子激活。 将进行研究 在A549细胞（人气道上皮细胞系）上和在初级气道中 上皮细胞 了解RSV的发病机制 诱导NF-κ-B活化和IL-8基因表达，未来的研究将 关注减轻RSV诱导的炎症的药理学手段， 气道。 候选人的长期计划将侧重于确定机制 病毒引起的气道炎症和损伤。

DESCRIPTION (Adapted from the applicant's abstract) The long term goal of the studies proposed, is to understand the mechanism of respiratory syncytial virus (RSV) induced interleukin-8 (IL-8) expression, as it is related to nuclear factor activation. RSV infection in children results in 90,000 hospital admissions and 4500 deaths on an annual basis in the U.S. The exact mechanism of RSV induced inflammation and injury is not known but appears to involve an intense inflammatory response. IL-8, a potent chemotactic and activating agent for leukocytes, is produced in increased amounts during RSV infection of airway cells in vitro and in vivo. Preliminary studies indicate that NF-k-B activation is critical for RSV induced IL-8 gene expression. The working hypothesis of this grant states that RSV proteins activate NF-k-B and other nuclear transcription factors which act cooperatively in airway cells to induce IL-8 gene transcription. In order to test this hypothesis, the following specific aims are proposed: 1) identify cis-active regulatory elements in the 5' flanking region of the IL-8 gene which are responsive to RSV infection, 2.) Define the role of viral replication in RSV induced IL-8 gene transcription and nuclear factor activation, 3.) Determine the role tyrosine phosphorylation of NF-k-b subunits in RSV induced NF-k-B activation and IL-8 gene expression, and 4.) Define the role of individual RSV gene products in stimulating IL-8 gene transcription through nuclear factor activation. Studies will be performed on A549 cells (a human airway epithelial cell line) and in primary airway epithelial cells. Having gained an understanding of mechanism of RSV induced NF-k-B activation and IL-8 gene expression, future studies will focus on pharmacologic means of amiliorating RSV induced inflammation in the airway. The candidates long term plan will focus on defining the mechanism of viral induced inflammation and injury in the airway.