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Rip Proteins in Innate Immune Signaling

撕裂先天免疫信号传导中的蛋白质

基本信息

批准号：
9184523
负责人：
MICHELLE ALICE KELLIHER
金额：
$ 41.88万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-12-15 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9184523
关键词：
AGFG1 gene Adaptor Signaling Protein Address Alpha Cell Apoptosis Caspase Cell Death Cell Death Signaling Process Cell Line Cells Cessation of life Complex DNA DNA Damage DNA Viruses Data Death Domain Defense Mechanisms Engineering Family Funding Genes Goals Host Defense Human IRF3 gene Immune Immune response Immune signaling Immunity Impairment In Vitro Infection Inflammation Inflammatory Inflammatory Response Injury Innate Immune Response Interferon Type I Interferons Laboratories Ligation Link Mediating Mitogen-Activated Protein Kinases Modeling Molecular Mus Mutation Natural Immunity Neonatal Nucleic Acids Pathway interactions Pattern Pattern recognition receptor Perinatal Phosphorylation Phosphotransferases Poly I-C Polyubiquitination Production Protein-Serine-Threonine Kinases Proteins Publishing RIPK1 gene RNA RNA Viruses Reactive Oxygen Species Receptor Signaling Recruitment Activity Role Signal Pathway Signal Transduction Small Interfering RNA Sterility Sting Injury System TANK-binding kinase 1 TLR3 gene TNF gene Testing Tissues Toll-like receptors Tretinoin Viral Virus Virus Diseases Virus Replication adaptive immune response antiviral immunity base cytokine ds-DNA genome-wide helicase in vivo innovation kinase inhibitor macrophage member monocyte novel public health relevance receptor response scaffold sensor transcription factor

项目摘要

DESCRIPTION (provided by applicant): The death domain containing serine/threonine kinase Ripk1 is the core component of TNF-induced signaling complexes mediating NFκB and MAP kinase activation, apoptosis and an alternative form of caspase independent cell death called necroptosis. In unbiased genome wide siRNA screens for regulators of necroptosis, Ripk1, its deubiquitinase Cyld, the related Ripk3 as well as other proteins belonging to the interferon and Toll-like receptor signaling systems were identified. These studies and those using an allosteric Ripk1 kinase inhibitor or Ripk3-deficient mice establish necroptosis as a prominent host defense against viral infection. Necroptosis requires the kinase activities of Ripk1 and Ripk3 but precisely how Rip kinases initiate and execute necroptotic cell death is unknown. We have shown that Ripk1 has additional signaling functions beyond TNF, in nucleic acid sensing pathways mediated by TLR3 and Rig-I. Our preliminary studies additionally implicate Ripk1 in a cytosolic DNA sensing pathway involving Sting, Tbk1 and Irf3. Collectively, these studies predict a central role for Ripk1 in innate anti-viral immunity, however the perinatal lethality associated with a Ripk1-deficiency has precluded in vivo analyses. Goals of the current proposal are to test a requirement for Ripk1 in the anti-viral innate immune response using the conditional Ripk1 mice we have generated. We have also introduced a mutation into the Ripk1 locus that impairs the kinase activity of Ripk1. Our preliminary studies in Ripk1 kinase inactive MEFs and macrophages find these cells protected from TNF- and TLR3-induced necroptosis, respectively. An additional objective of this proposal is to examine the contribution of viral-initiated necroptosis to host defense in these newly engineered Ripk1 kinase inactive mice. In addition to virus-induced injury and inflammation, Rip kinases respond to non-microbial signals called danger-associated molecular patterns (DAMPs) released upon tissue injury. The long-term goal of these studies is to selectively inhibit Rip kinases in sterile inflammation without impairing innate immunity.

描述(申请人提供)：包含丝氨酸/苏氨酸激酶Ripk1的死亡结构域是肿瘤坏死因子诱导的信号复合体的核心成分，介导NFκB和MAP激酶的激活、细胞凋亡和另一种形式的caspase非依赖性细胞死亡，称为坏死性下垂。在无偏见的全基因组siRNA筛选中，鉴定了Ripk1、其去泛素酶CyLD、相关的RIPK3以及属于干扰素和Toll样受体信号系统的其他蛋白质。这些研究和使用变构Ripk1激酶抑制剂或RIPK3缺陷小鼠的研究证实，坏死性下垂是抵抗病毒感染的突出宿主防御。坏死性下垂需要Ripk1和RIPK3的激酶活性，但RIPKs如何启动和执行坏死性细胞死亡的确切方式尚不清楚。我们已经证明，在TLR3和RIG-I介导的核酸传感通路中，Ripk1在肿瘤坏死因子之外还具有额外的信号功能。我们的初步研究还发现，Ripk1参与了Sting、Tbk1和IRF3的胞质DNA传感通路。总的来说，这些研究预测了Ripk1在先天抗病毒免疫中的核心作用，然而与Ripk1缺乏相关的围产期致死性排除了活体分析的可能性。当前提案的目标是使用我们培育的条件Ripk1小鼠来测试Ripk1在抗病毒先天免疫反应中的需求。我们还在Ripk1基因座引入了一种突变，该突变会削弱Ripk1的激酶活性。我们在Ripk1激酶失活的MEF和巨噬细胞中的初步研究发现，这些细胞分别受到肿瘤坏死因子和TLR3诱导的坏死性下垂的保护。这项建议的另一个目标是检查病毒引发的坏死性下垂对这些新设计的Ripk1激酶失活小鼠的宿主防御的贡献。除了病毒引起的损伤和炎症，Rip激酶还对组织损伤时释放的称为危险相关分子模式(DAMP)的非微生物信号做出反应。这些研究的长期目标是在不损害天然免疫的情况下，选择性地抑制无菌炎症中的Rip激酶。