Regulation of Innate Immunity by Pyrin Proteins

Pyrin 蛋白对先天免疫的调节

• 批准号: 7883582
• 负责人: JONATHAN A HARTON
• 金额: $ 35.19万
• 依托单位: ALBANY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7883582
• 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; Figs - dietary; 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; 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; Testing; Ticks; Toll-like receptors; Transfection; Transgenic Mice; Tularemia; Virulent; Yersinia pestis; aerosolized; base; cytokine; experience; extracellular; in vivo; innovation; macrophage; marenostrin; member; microbial; mouse model; numb protein; p65; pathogen; peripheral blood; prevent; protein function; public health relevance; receptor; receptor function; research study; response; secretion process; vector transmission

DESCRIPTION (provided by applicant): 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-?B and MAPK signaling pathways leading to the transcription and secretion of multiple inflammatory cytokines (e.g. TNF1, IL-6, and IL-8). Unlike TLRs, NLRs can also activate multiprotein inflammasome complexes that processes proIL-12 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-?B. Recently, the discovery of pyrin only proteins (POPs) that influence both NF-?B 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-?B 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-?B 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-?B 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. PUBLIC HEALTH RELEVANCE: Inflammatory responses resulting from injury or infection are a significant threat to human health. We propose to study a small protein called POP2 which is expressed in inflammatory cells and can regulate cellular events leading to inflammation. This study is therefore relevant to a wide range of inflammatory diseases and conditions, ranging from infection to cardiovascular disease.

描述（由申请人提供）：TLR和NLR家族成员对细胞外和细胞内病原体的识别启动先天免疫和炎症反应。tlr和nlr都能激活NF-？B和MAPK信号通路导致多种炎症细胞因子（如TNF1、IL-6和IL-8）的转录和分泌。与tlr不同，nlr也可以激活多蛋白炎性体复合物，将proIL-12和proIL-18加工成活性形式。在不到五年的时间里，NLRs与遗传性自身炎症疾病和对越来越多的病原体的先天免疫反应有关，包括炭疽芽孢杆菌、鼠疫耶尔森菌和土拉菌。炎性小体的组装源于含有NLR蛋白的pyrin与ASC（凋亡斑点蛋白与CARD）的相互作用，随后是Caspase-1的募集和激活。炎性小体复合体也可能参与诱导一种依赖caspase-1的细胞凋亡。ASC与nlr和Pyrin蛋白的相互作用也可以激活NF- B。最近，发现了影响NF-？B和炎性小体的功能提示了宿主调节促炎反应和病原体颠覆的途径。这项建议的长期目标是了解依赖于pyrin蛋白的先天免疫反应的分子调控。此外，对炎性小体调节的理解将扩展到宿主-病原体相互作用，其中炎性小体的功能或破坏被证明对免疫或疾病至关重要。具体来说，我们已经确定了第二种人类POP (POP2)，它可以抑制NF-？bp65活性，与ASC相互作用，并阻止一些NLR激活的炎性小体的激活。我们将验证POP2通过干扰炎性小体介导的caspase-1激活和减弱NF-？B信号，从而抑制有害炎症和预防或减少巨噬细胞死亡在先天免疫反应。结合广泛的分子和体内方法，我们将解决以下目标：1)建立NF-？2)建立POP2调控炎性小体活化的分子基础。3)建立POP2在体内调节炎性先天免疫应答中的作用。公共卫生相关性：损伤或感染引起的炎症反应是对人类健康的重大威胁。我们建议研究一种叫做POP2的小蛋白，它在炎症细胞中表达，可以调节导致炎症的细胞事件。因此，这项研究与广泛的炎症性疾病和病症相关，从感染到心血管疾病。