Innate antiviral response and predisposition to neoplasia in IRF-5 deficient mous

描述(申请人提供)：我们研究的长期目标是了解针对病原体的天然免疫防御的分子机制。目前的应用集中在检查IRF-5在体内先天抗病毒反应和肿瘤发生中的作用。干扰素调节因子(IRF)是病毒和干扰素诱导的信号通路的转录介质，参与抗病毒防御、免疫反应、细胞生长和细胞凋亡。IRF-3、IRF-5和IRF-7是病毒介导的信号转导分子，在I型干扰素基因的表达中起着至关重要的作用。此外，IRF-5是肿瘤抑制因子P53的下游靶点。虽然IRF-3和IRF-7在感染反应中的功能已有很好的描述，但IRF-5在体内的作用尚不清楚。为了研究IRF-5在体内的功能，我们培育了IRF-5基因零等位基因的小鼠。IRF-5突变纯合子的小鼠是存活的，发育正常。目的1分析IRF-5在先天抗病毒反应中的作用，鉴定淋巴细胞亚群，确定病毒感染后的抗病毒反应；目的2研究IRF-5在Toll受体样7(TLR7)介导的信号转导中的作用，以及TLR7介导的抗病毒和炎症反应的分子机制。IRF-5是否在TLR7介导的PDC中对siRNA的识别中起关键作用的问题将被解决。目的3将评估IRF5基因缺失小鼠对自发肿瘤发生的易感性；这些肿瘤的表型将与p53基因缺失小鼠形成的肿瘤的表型进行比较。IRF-5基因缺失的小鼠对逆转录病毒诱导的B细胞淋巴生成的敏感性将被检测。这些研究的结果应该清楚地确定IRF-5在抗病毒免疫反应中的作用，以及它在TLR7介导的抗病毒途径中的作用。这也将有助于我们理解IRF-5在P53生长调控通路中的可能作用及其在病毒诱导的淋巴肿瘤发生中的作用。了解IRF-5参与先天抗病毒反应和炎症反应的机制，将为有害免疫反应的治疗控制提供新的理性基础。此外，揭示IRF-5在肿瘤监视和P53介导的生长调节通路中的可能作用，可能为控制和治疗功能不活跃的P53的肿瘤提供新的途径。

DESCRIPTION (provided by applicant): The long-term objective of our studies is to understand the molecular mechanism of the innate immune defense against pathogen. The present application is focused on an examination of the in vivo role of IRF-5 in innate antiviral response and in tumorigenesis. Interferon regulatory factors (IRF) are transcriptional mediators of virus and IFN-induced signaling pathways, involved in the antiviral defense, immune response, cell growth and apoptosis. IRF-3, IRF-5 and IRF-7 function as direct transducers of virus mediated signaling and play crucial role in the expression of type I IFN genes. In addition IRF-5 is a downstream target of tumor suppressor, p53. While the functions of IRF-3 and IRF-7 in response to infection are well characterized, the role of IRF-5 in vivo is unknown. To investigate the function of IRF-5 in vivo, we have generated mice with the null allele of the IRF-5 gene. Mice homozygous for the mutated IRF-5 are viable and developmentally normal. Aim 1 will analyze the role of IRF-5 in the innate antiviral response, characterize the lymphoid cells subsets, and determine the antiviral response to viral infections; Aim 2 will examine the role of IRF-5 in the in Toll receptor like 7 (TLR7) mediated signaling and the molecular mechanism of the TLR7 mediated induction of the antiviral and inflammatory responses. The question whether IRF-5 plays a critical role in the TLR7 mediated recognition of siRNA in PDC will be addressed. Aim 3 will asses the susceptibility of IRF5 null mice to spontaneous tumorigenesis; the phenotype of these tumors will be compared with the phenotype of tumors formed in p53 null mice. The susceptibility of the IRF-5 null mice to the retroviral induced B cell lymphogenesis will be examined. Results from these studies should clearly define the role of IRF-5 in the antiviral immune response, and its role in the TLR7 mediated antiviral pathways. It will also contribute to our understanding of the possible role of IRF-5 in the growth regulatory pathway of p53 and its contribution to virus induced lymphomagenesis. Understanding the mechanism by which IRF-5 participates in the innate antiviral response and inflammation will provide a new rational base for the therapeutic control of harmful immune responses. Furthermore, uncovering the possible role of IRF-5 in tumor surveillance and p53 mediated growth regulatory pathways may provide a new approach for the control and therapy of tumors with functionally inactive p53.