EXPRESSION & FUNCTION OF A CMV CHEMOKINE IN PATHOGENESIS

描述：提出的研究调查的表达和 小鼠巨细胞病毒编码的趋化因子同源物的功能作用 (MCMV)。麦克唐纳博士已经注意到，推导出的MCMV开放序列 阅读框架与CC(Beta)类成员高度同源 趋化因子。这是第一个病毒可能产生 细胞因子及其受体。β趋化因子是哺乳动物的小分子。 对白细胞有趋化作用，包括单核/巨噬细胞、细胞 在巨细胞病毒感染中起着重要作用。利用体外趋化作用， 钙动员和结合分析，麦克唐纳博士将确定 无论这种名为MCK-1的趋化因子同系物是表现出激动剂还是 原代培养细胞内源性趋化因子受体的拮抗活性 小鼠巨噬细胞，以及巨噬细胞系。核糖核酸的表达 编码MCK-1的基因将在感染组织中用分子方法表征 培养细胞，以及在感染小鼠的组织中。MCK-1的作用 在MCMV中，将通过给药MCK-1来研究其发病机制 中和抗体和缺失重组MCMV的产生 功能性MCK-1。对组织病毒滴度、半数致死量及炎症反应的影响 回应将会被确定。这些研究将为我们提供对 趋化因子在巨细胞病毒发病机制中的作用，为治疗提供可能 和/或对这种人类病原体的预防性干预。

DESCRIPTION: The research proposed investigates the expression and functional role of a chemokine homologue encoded by murine cytomegalovirus (MCMV). Dr. MacDonald has noted that the deduced sequence of a MCMV open reading frame is highly homologous to members of the CC (Beta) class of chemokines. This is the first example of a virus possibly producing a cytokine and its receptor. Beta chemokines are small mammalian molecules which are chemotactic for leukocytes, including monocyte/macrophages, cells that play a prominent role in CMV infection. Utilizing in vitro chemotaxis, calcium mobilization and binding assays, Dr. MacDonald will determine whether this chemokine homologue, designated MCK-1, exhibits agonist or antagonist activity for endogenous chemokine receptors present on primary murine macrophages, as well as macrophage cell lines. The expression of RNA encoding MCK-1 will be characterized by molecular methods in infected tissue culture cells, as well as in tissues from infected mice. The role of MCK-1 in MCMV pathogenesis will be investigated by administration of MCK-1 neutralizing antibodies and by the generation of a recombinant MCMV lacking functional MCK-1. Effects on tissue viral titers, LD50 and the inflammatory response will be determined. These studies will provide insight into the role of chemokines in HCMV pathogenesis, leading to possible therapeutic and/or preventative interventions for this human pathogen.