MECHANISM OF RSV INDUCED IL-8 GENE TRANSCRIPTION

描述 (摘自申请者的摘要)研究的长期目标 提出，是为了了解呼吸道合胞病毒的机制 呼吸道合胞病毒(RSV)诱导的白介素8(IL-8)表达，因为它与核相关 因子激活。9万家医院发生儿童呼吸道合胞病毒感染 美国每年的入院人数和4500人的死亡人数 RSV诱导的炎症和损伤的机制尚不清楚，但似乎 涉及到强烈的炎症反应。IL-8，一种强大的趋化性和 白细胞激活剂，在呼吸道合胞病毒过程中产生的量增加 体外和体内的呼吸道细胞感染。初步研究 提示核因子-k-B的激活在RSV诱导的IL-8基因表达中起关键作用 表情。这项研究的工作假设是，RSV蛋白 激活核因子-k-B和其他核转录因子 在呼吸道细胞中协同诱导IL-8基因转录。按顺序 为了验证这一假设，提出了以下具体目标：1) 确定5‘侧翼区域中的顺式活性调控元件 对RSV感染有反应的IL-8基因。定义的角色 呼吸道合胞病毒诱导IL-8基因转录和核因子的病毒复制 激活，按3。)确定核因子-k-b的酪氨酸磷酸化作用 RSV亚基诱导核因子-k-B活化和IL-8基因表达。 明确单个RSV基因产物在刺激IL-8基因中的作用 通过核因子激活进行转录。将进行研究 A549细胞(人呼吸道上皮细胞株)和原代呼吸道 上皮细胞。对呼吸道合胞病毒的致病机理有了一定的了解 诱导核因子-k-B活化和IL-8基因表达，未来研究将 关注减轻呼吸道合胞病毒引起的炎症的药理手段 气道口。候选人的长期计划将重点放在确定机制上 病毒引起的呼吸道炎症和损伤。

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.