Regulation of Innate Immunity by Pyrin Proteins

Pyrin 蛋白对先天免疫的调节

• 批准号: 7736107
• 负责人: JONATHAN A HARTON
• 金额: $ 36.5万
• 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/7736107
• 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家族成员的细胞外病原体识别启动先天免疫和炎症反应。 TLR和NLR都激活NF-？B和MAPK信号传导途径，导致多种炎症细胞因子的转录和分泌（例如TNF1，IL-6和IL-8）。与TLR不同，NLR还可以激活将proil-12和proil-18处理为活性形式的多蛋白炎症体复合物。在不到五年的时间里，NLR与遗传性自身炎症性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，耶尔森氏菌，鼠疫耶尔森氏菌和francisella tolareensis。炎症体组装是由含有NLR蛋白与ASC（凋亡斑点蛋白与卡片）的吡啶相互作用的相互作用，然后募集和激活caspase-1。炎性体复合物也可能参与诱导caspase-1依赖性凋亡的形式。 ASC与NLR的相互作用和蛋白质吡啶也可以激活NF-？b。最近，仅影响NF-？B和炎性体功能的pyrin的蛋白质（POP）提出了一种宿主调节促炎反应和病原体颠覆的途径。该提案的长期目标是了解仅依赖于吡啶蛋白的先天免疫反应的分子调节。此外，对炎性体调节的理解将扩展到宿主病原体相互作用，在这种相互作用中，炎性体功能或颠覆对免疫或疾病至关重要。具体而言，我们已经确定了第二个人类POP（POP2），该POP（POP2）抑制了NF-？B p65活性，与ASC相互作用，并防止了许多NLR激活的炎症体的激活。我们将检验以下假设：POP2通过干扰炎症体介导的caspase-1激活和减弱NF-？b信号来负面调节促炎反应，从而减轻了有害炎症并防止或减少先天免疫反应期间巨噬细胞死亡。结合了基于广泛的分子和体内方法，我们将解决以下目的：1）建立POP2抑制Nf- b抑制的分子基础22）建立POP2调节炎性体激活的分子基础。 3）确定POP2在调节炎症性先天免疫反应中的体内作用。公共卫生相关性：受伤或感染引起的炎症反应是对人类健康的重大威胁。我们建议研究一种称为POP2的小蛋白，该蛋白在炎症细胞中表达，并可以调节导致炎症的细胞事件。因此，这项研究与从感染到心血管疾病的多种炎症性疾病和状况有关。