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

IRF-5 缺陷小鼠的先天抗病毒反应和肿瘤易感性

• 批准号: 7149544
• 负责人: Paula M Pitha-Rowe
• 金额: $ 40.88万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7149544
• 关键词: genes; immune response; interferons; neoplasm /cancer; role

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.

描述（由申请人提供）：我们研究的长期目标是了解针对病原体的先天免疫防御的分子机制。本申请集中于检查IRF-5在先天抗病毒反应和肿瘤发生中的体内作用。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、细胞生长和凋亡。 IRF-3、IRF-5 和 IRF-7 作为病毒介导的信号转导的直接转导子，在 I 型 IFN 基因的表达中发挥至关重要的作用。此外，IRF-5 是肿瘤抑制因子 p53 的下游靶标。虽然 IRF-3 和 IRF-7 响应感染的功能已得到很好的表征，但 IRF-5 在体内的作用尚不清楚。为了研究 IRF-5 的体内功能，我们培育了具有 IRF-5 基因无效等位基因的小鼠。 IRF-5 突变的纯合小鼠可存活且发育正常。目标 1 将分析 IRF-5 在先天抗病毒反应中的作用，表征淋巴细胞亚群，并确定对病毒感染的抗病毒反应；目标 2 将研究 IRF-5 在 Toll 受体样 7 (TLR7) 介导的信号传导中的作用以及 TLR7 介导的抗病毒和炎症反应诱导的分子机制。 IRF-5 是否在 PDC 中 TLR7 介导的 siRNA 识别中发挥关键作用的问题将得到解决。目标 3 将评估 IRF5 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细胞淋巴生成的敏感性。这些研究的结果应该清楚地界定 IRF-5 在抗病毒免疫反应中的作用，及其在 TLR7 介导的抗病毒途径中的作用。它还将有助于我们了解 IRF-5 在 p53 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 参与先天抗病毒反应和炎症的机制将为有害免疫反应的治疗控制提供新的合理基础。此外，揭示IRF-5在肿瘤监测和p53介导的生长调节途径中的可能作用可能为控制和治疗功能失活的p53肿瘤提供新方法。