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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

基本信息

批准号：
8082049
负责人：
Paula M Pitha-Rowe
金额：
$ 14万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-11 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8082049
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

项目摘要

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先天免疫防御病原体的分子机制。目前的应用主要集中在研究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、免疫应答、细胞生长和凋亡。IRF-3、IRF-5和IRF-7是病毒介导的信号转导体，在I型IFN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在应对感染方面的功能已被很好地表征，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，我们培育了带有IRF-5基因空等位基因的小鼠。突变的IRF-5纯合的小鼠是活的和发育正常的。目的1将分析IRF-5在先天抗病毒反应中的作用，表征淋巴样细胞亚群，并确定对病毒感染的抗病毒反应；目的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的分子机制。关于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。目的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。IRF-5缺失小鼠对逆转录病毒诱导的B细胞淋巴发生的易感性将被检测。这些研究的结果应该清楚地定义IRF-5在抗病毒免疫应答中的作用，以及它在TLR7介导的抗病毒途径中的作用。这也将有助于我们了解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在肿瘤监测和p53介导的生长调控途径中的可能作用，可能为p53功能失活的肿瘤的控制和治疗提供新的途径。