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Regulation of Innate Immunity by Pyrin Proteins

Pyrin 蛋白对先天免疫的调节

基本信息

批准号：
8288318
负责人：
JONATHAN A HARTON
金额：
$ 34.84万
依托单位：
ALBANY MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8288318
关键词：
Address Apoptosis Apoptotic Attenuated Bacillus anthracis Biological Breathing CCL2 gene Cardiovascular Diseases Caspase Caspase-1 Cell Death Cell Line Cells Cessation of life Complex Data Death Domain Disease Event Family Francisella Francisella tularensis Generations Genetic Transcription Goals Health Human IL8 gene Immune Immune response Immunity Infection Inflammation Inflammatory Inflammatory Response Inflammatory Response Pathway Inherited Injury Insect Vectors Interleukin-18 Interleukin-6 Laboratories Leukocytes Link Listeria monocytogenes MAP Kinase Gene MAPK Signaling Pathway Pathway Mediating Modeling Molecular Mus NF-kappa B Natural Immunity Organism Pathogenesis Pathway interactions Pattern recognition receptor Play Positioning Attribute Process Production Proteins Receptor Activation Regulation Reporting Research Role Salmonella enterica Shigella flexneri Signal Transduction Small Interfering RNA System TLR2 gene TNF gene Testing Ticks Toll-like receptors Transcription Factor AP-1 Transfection Transgenic Mice Tularemia Virulent Yersinia pestis aerosolized base cytokine experience extracellular in vivo innovation macrophage marenostrin member mouse model p65 pathogen peripheral blood prevent protein function receptor receptor function research study response secretion process vector transmission

项目摘要

SUMMARY Extracellular and intracellular pathogen recognition by members of the TLR and NLR families initiate innate immune and inflammatory responses. TLRs and NLRs both activate the NF-kB and MAPK signaling pathways leading to the transcription and secretion of multiple inflammatory cytokines (e.g. TNF¿, IL-6, and IL-8). Unlike TLRs, NLRs can also activate multiprotein inflammasome complexes that processes proIL-1¿ and proIL-18 to their active forms. In less than five years, NLRs have been linked to hereditary autoinflammatory diseases and innate immune response towards a growing number of pathogens, including Bacillus anthracis, Yersinia pestis, and Francisella tularensis. Inflammasome assembly results from interaction of a pyrin containing NLR protein with ASC (apoptotic speck protein with a CARD) followed by recruitment and activation of Caspase-1. The inflammasome complex may also be involved in inducing a form of caspase-1 dependent apoptosis. ASC interactions with NLRs and the protein Pyrin can also activate NF-kB. Recently, the discovery of pyrin only proteins (POPs) that influence both NF-kB and inflammasome functions has suggested an avenue for host regulation of the proinflammatory response and pathogen subversion thereof. The long-term objective of this proposal is to understand the molecular regulation of innate immune responses dependent upon pyrin only proteins. Further, understanding of inflammasome regulation will be extended to host-pathogen interactions where inflammasome function or subversion is demonstrated to be critical for immunity or disease. Specifically, we have identified a second human POP (POP2) which inhibits NF-kB p65 activity, interacts with ASC, and prevents the activation of a number of NLR activated inflammasomes. We will test the hypothesis that POP2 negatively regulates proinflammatory responses by interfering with both inflammasome- mediated caspase-1 activation and attenuating NF-kB signals, thus dampening harmful inflammation and preventing or reducing macrophage death during innate immune responses. Combining broad based molecular and in vivo approaches, we will address the following aims: 1) Establish the molecular basis for NF-kB inhibition by POP2 2) Establish the molecular basis for POP2 regulation of inflammasome activation. 3) Establish the in vivo role of POP2 in modulating inflammatory innate immune responses.

摘要 TLR和NLR家族成员的细胞外和细胞内病原体识别启动先天免疫和炎症反应。TLRs和NLRs都激活了NF-kB和MAPK信号通路导致多种炎性细胞因子(如肿瘤坏死因子、白介素6和白介素8)的转录和分泌。不像 TLRs，NLRs还可以激活多蛋白炎症体复合体，使proIL-1和proIL-18处理为它们的活跃形式。在不到五年的时间里，NLRs与遗传性自体炎症性疾病和对越来越多的病原体的先天免疫反应，包括炭疽杆菌、鼠疫耶尔森菌、和图拉氏方济氏菌。含有NLR蛋白的比林相互作用导致炎性小体组装与ASC(带有卡片的凋亡斑点蛋白)一起募集和激活Caspase-1。这个炎性小体复合体也可能参与诱导一种形式的caspase-1依赖的细胞凋亡。ASC 与NLRs和蛋白质派林的相互作用也可以激活核因子-kB。最近，只有吡喃的发现同时影响核因子-kB和炎症体功能的蛋白质(POP)为宿主提供了一条途径对促炎反应及其病原体颠覆的调节。这样做的长期目标是建议理解仅依赖于吡喃的先天免疫反应的分子调控。蛋白质。此外，对炎症体调节的理解将扩展到宿主与病原体的相互作用。炎症小体功能或颠覆被证明是免疫或疾病的关键。具体地说，我们已经确定了第二个人类POP(POP2)，它抑制NF-kB p65的活性，与 ASC，并阻止一些NLR激活的炎性小体的激活。我们将检验这一假设 POP2通过干扰炎症体-2来负向调节促炎反应。介导caspase-1激活和减弱核因子-kB信号，从而抑制有害的炎症以及防止或减少先天性免疫反应中巨噬细胞的死亡。组合体宽广基于分子和体内的方法，我们将解决以下目标：1)建立分子基础针对POP2对核因子-kB的抑制2)建立POP2调节炎症体的分子基础激活。3)确定POP2在体内调节炎性先天免疫反应中的作用。