Cellular Response to Infectious Triggers

描述(申请人提供)：我们研究的长期目标是描述调节对入侵病原体的免疫防御的分子机制。这项研究的重点是干扰素调节因子家族转录因子(IRF)在病毒感染的先天和后天反应中的作用。这些因子不仅参与了I型干扰素基因的诱导，还参与了其他细胞因子、趋化因子和直接参与抗病毒和抗炎反应的基因的诱导。在过去的几年里，我们先后分离了IRF-3、IRF-7和IRF-5，并证明这些因子是病毒诱导信号的直接转运体。这些因子的功能不是多余的，因为这些因子在不同的细胞类型中表达，并刺激一系列不同的基因。在这三个因素中，IRF-7在诱导IFNA方面发挥了限制作用，而IFNA被证明对先天性免疫反应和获得性免疫反应都是重要的。我们的假设是，这三个IRF，特别是IRF-7，正在调节这两种免疫反应。这项应用的关键目标是验证这一假说，并确定红外线受体激活目标基因以响应病原体的分子机制。 这项研究有三个目标。 在目标1中，我们将研究IRF-7介导的抗病毒基因激活所涉及的分子机制。 在目标2中，我们将确定Toll 3和Toll 9分别对dsRNA和CpG DNA的反应是否导致IRF-3、IRF-5和IRF-7的激活。 在目标3中，我们将确定病毒、dsRNA和CpG DNA对巨噬细胞和树突状细胞的刺激是否针对相似或不同的一组抗病毒基因。 我们相信，对IRF因子在病原体诱导的细胞反应中的作用的基本了解将为免疫和炎症性疾病的治疗提供新的治疗平台。

DESCRIPTION (provided by applicant): The long time goal of our studies is to delineate the molecular mechanism that regulates the immune defense against invading pathogens. The study proposed is focused on the role of the family transcription factors of interferon regulatory factors (IRF) in the innate and acquired responses to viral infection. These factors were shown to participate not only in the induction of Type I IFN genes but also in the induction of other cytokines, chemokines and genes directly involved in the antiviral and anti-inflammatory responses. Over the past years we have sequentially isolated IRF-3, IRF-7 and IRF-5 and have shown that these factors serve as direct transporters of virus induced signaling. The function of these factors is not redundant since these factors are expressed in different cell types and stimulate a profile of distinct genes. Among these three factors IRF-7 plays a limiting role in the induction of IFNa that was shown to be important both for the innate and adaptive immune responses. It is our hypothesis that these three IRFs, especially then IRF-7, are regulating both of these immune responses. The key objective of this application is to validate this hypothesis and to determine the molecular mechanism by which IRFs activates the targeted genes in response to pathogens. The study has three aims. In Aim#1 we shall examine the molecular mechanism involved in the IRF-7 mediated activation of antiviral genes. In Aim#2 we shall determine whether Toll 3 and Toll 9 responses to dsRNA and CpG DNA respectively results in the activation of IRF-3, IRF-5 and IRF-7. In Aim #3 we shall determine whether the stimulation of macrophages and dendritic cells by virus, dsRNA and CpG DNA targets similar or distinct set of antiviral genes. We believe that the basic understanding of the role of IRF factors in pathogen induced cellular responses will provide a new therapeutic platform for the treatment of the immune and inflammatory disease.