Varicella Zoster Virus Interactions With Human Skin

描述（由申请方提供）：水痘带状疱疹病毒（VZV）是一种重要的人类病原体，仅限于在人体组织和细胞中生长。该项目的主要目标是了解VZV如何在人体皮肤中生长，以及它对皮肤细胞的细胞内环境有什么影响。我们的假设是VZV与宿主的分子相互作用在皮肤器官培养中与在培养细胞中是根本不同的。我们将通过建立VZV复制的皮肤器官培养（SOC）模型来解决这个问题，研究VZV在这个皮肤模型中的组装，并测试VZV突变体的表型。SOC模型也将使我们能够研究VZV感染对宿主细胞的影响。我们的第二个目的是研究VZV感染对皮肤细胞信号转导通路的影响。我们将测量酪氨酸磷酸化的水平，这是信号转导的早期事件，然后使用一组抗体来研究三个主要的下游途径。最后，将使用信号转导激酶的化学抑制剂来确定它们对VZV复制的影响。最终，皮肤器官培养模型可以帮助我们通过识别VZV毒力基因来提高疫苗安全性，并为靶向病毒和细胞蛋白的抗病毒药物提供新的思路。

DESCRIPTION (provided by applicant): Varicella zoster virus (VZV) is an important human pathogen that is restricted to growth in human tissues and cells. The primary goal of this project is to learn how VZV grows in human skin, and what effects it has on the intracellular environment of skin cells. Our hypothesis is that the molecular interaction of VZV with the host is fundamentally different in skin organ culture than in cultured cells. We will approach this issue by developing the skin organ culture (SOC) model of VZV replication, study the assembly of VZV in this skin model, and test the phenotype of VZV mutants. The SOC model will also allow us to study the effects of VZV infection on the host cells. Our second aim is to investigate the effects of VZV infection on signal transduction pathways in skin cells. We will measure the level of tyrosine phosphorylation, an early event in signal transduction, and then use a panel of antibodies to study the three major downstream pathways. Finally, chemical inhibitors of the signal transduction kinases will be used to determine their effect on VZV replication. Ultimately, the skin organ culture model may help us improve vaccine safety by identifying VZV virulence genes, and provide new ideas for antiviral drugs that target viral and cellular proteins.