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

描述（由申请人提供）：我们研究的长期目标是了解先天免疫防御病原体的分子机制。本申请集中于检查IRF-5在先天性抗病毒应答和肿瘤发生中的体内作用。干扰素调节因子（Interferon Regulatory Factor，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、免疫应答、细胞生长和凋亡。IRF-3、IRF-5和IRF-7作为病毒介导的信号传导的直接转导子，在I型IFN基因的表达中起关键作用。此外，IRF-5是肿瘤抑制因子p53的下游靶标。虽然IRF-3和IRF-7在响应感染中的功能已得到充分表征，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，我们产生了IRF-5基因无效等位基因的小鼠。突变的IRF-5纯合子小鼠是可存活的并且发育正常。目的1将分析IRF-5在先天性抗病毒应答中的作用，表征淋巴细胞亚群，并确定对病毒感染的抗病毒应答;目的2将检查IRF-5在Toll受体样7（TLR 7）介导的信号传导中的作用以及TLR 7介导的抗病毒和炎症应答的分子机制。IRF-5是否在PDC中TLR 7介导的siRNA识别中起关键作用的问题将得到解决。目的3将评估IRF 5缺失小鼠对自发性肿瘤发生的易感性;将这些肿瘤的表型与p53缺失小鼠中形成的肿瘤的表型进行比较。将检查IRF-5缺失小鼠对逆转录病毒诱导的B细胞淋巴细胞生成的易感性。这些研究的结果应明确定义IRF-5在抗病毒免疫应答中的作用，以及其在TLR 7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的生长调节途径中的可能作用及其对病毒诱导的淋巴瘤发生的贡献。了解IRF-5参与先天性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介导的生长调节途径中的可能作用可能为控制和治疗具有功能失活的p53的肿瘤提供新的方法。

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.