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: 7879743
• 负责人: Paula M Pitha-Rowe
• 金额: $ 3.8万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2010-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7879743
• 关键词: Abbreviations; Address; Age; Alleles; Anti-Bacterial Agents; Antiviral Agents; Antiviral Response; Apoptosis; Apoptotic; Asses; B-Cell Lymphomas; B-Lymphocytes; BM-5; Binding Proteins; Biological; CD4 Positive T Lymphocytes; Candidate Disease Gene; Cells; DNA; Data; Development; Family; Fibroblasts; G2/M Arrest; Genes; Genetic Recombination; Genetic Transcription; Growth; Helper-Inducer T-Lymphocyte; Herpesviridae; Human; Immune; Immune response; Impairment; In Vitro; Induction of Apoptosis; Infection; Inflammation; Inflammatory Response; Interferon-alpha; Interferons; Interleukins; Knockout Mice; Lymphocytic choriomeningitis virus; Lymphoid Cell; Lymphomagenesis; Measures; Mediating; Mediator of activation protein; Molecular; Murid herpesvirus 1; Mus; Mutate; Neoplasms; Newcastle disease virus; Null Lymphocytes; Ovalbumin; Pathway interactions; Phenotype; Play; Predisposition; Prevention; Property; Protein p53; Regulatory Pathway; Research Personnel; Retroviridae; Role; Signal Pathway; Signal Transduction; Simplexvirus; Small Interfering RNA; Stream; TLR3 gene; TLR4 gene; TP53 gene; Testing; Therapeutic; Toll-like receptors; Transducers; Vesicular stomatitis Indiana virus; Viral; Virus; Virus Diseases; base; cell growth; chemokine; cytokine; gene induction; human IRF3 protein; human TLR7 protein; in vivo; interferon regulatory factor-3; interferon regulatory factor-7; member; mouse model; new therapeutic target; novel strategies; pathogen; programs; resiquimod; response; tumor; tumorigenesis; tumorigenic

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 IIFN 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 w 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 the spontaneous tumorigenesis ; the phenotype of these tumors will be compared with the phenotype of tumors formed in p53 null mice. The sussceptibility 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 wil also contribute to our understanding of the possible role of IRF-5 in the gorowth 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.

我们的长期研究目标是了解先天免疫的分子机制 对病原体的防御本申请集中于检查IRF-5的体内作用 在先天性抗病毒反应和肿瘤发生中。干扰素调节因子（IRF）是转录的 病毒和IFN诱导的信号传导途径的介质，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发挥作用 并在IIFN基因的表达中起关键作用。此外，IRF-5是肿瘤的下游靶点 抑制基因，p53。虽然IRF-3和IRF-7在响应感染中的功能被很好地表征，但IRF-3和IRF-7在响应感染中的功能被很好地表征。 IRF-5在体内的作用尚不清楚。为了研究IRF-5在体内的功能，我们已经产生了具有W IRF-5基因的无效等位基因突变的IRF-5纯合子小鼠存活并发育 正常目标1。将分析IRF-5在先天性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;目的2.将审查综合资源框架5在 Toll受体样7（TLR 7）介导的信号传导和TLR 7介导的分子机制 诱导抗病毒和炎症反应。IRF-5是否在这方面发挥关键作用的问题， 将解决PDC中TLR 7介导的siRNA识别。目标3.将评估IRF 5的易感性 空小鼠自发肿瘤发生;这些肿瘤的表型将与 在p53缺失小鼠中形成的肿瘤表型。IRF-5基因敲除小鼠对逆转录病毒的易感性 将检测诱导的B细胞淋巴生成。这些研究的结果应明确界定 IRF-5在抗病毒免疫应答中的作用及其在TLR 7介导的抗病毒途径中的作用。它也将 有助于我们理解IRF-5在p53的gorowth调节通路中的可能作用， 其对病毒诱导的淋巴瘤形成的贡献。了解IRF-5 参与先天性抗病毒反应，炎症将为抗病毒治疗提供新的理性基础。 有害免疫反应的治疗控制。此外，揭示综合RF-5在以下方面可能发挥的作用： 肿瘤监视和p53介导的生长调节途径可能为肿瘤的治疗提供新的途径。 控制和治疗具有功能失活p53的肿瘤。