Inflammasome function and SJIA
炎症小体功能和 SJIA
基本信息
- 批准号:8285388
- 负责人:
- 金额:$ 21.33万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-08-01 至 2014-05-31
- 项目状态:已结题
- 来源:
- 关键词:AccountingAdaptor Signaling ProteinAffectAgeApoptosisArthritisBiochemicalBiologyBloodC-reactive proteinCandidate Disease GeneCaspase-1Cell AgingCell DeathCellsChildChronicChronic Childhood ArthritisCleaved cellClinicalComplexComplicationDataDefectDiseaseEmployee StrikesEvaluationEventExanthemaFeverGenesGeneticGenetic ScreeningGoalsHereditary DiseaseImmuneInflammationInflammation MediatorsInflammatoryInstitutesIntegration Host FactorsInterleukin-1Interleukin-18KnowledgeLaboratoriesLeadLightMacrophage ActivationMeasuresMediatingMolecularMultiprotein ComplexesMutationNormal CellPathogenesisPathway interactionsPatientsPeptide Signal SequencesPericarditisPlayPleurisyPrevention approachProcessProductionProteinsPurinoceptorRegulationRelapseResolutionRheumatoid ArthritisRoleSmall Interfering RNAStagingStimulusSubcellular structureSyndromeTestingWorkanakinraarthritis therapybasecell agecytokinedriving forcefollow-upgenome-wideinhibitor/antagonistinnovationinterestmacrophagemonocytemortalitynovelporinresponsesecretion process
项目摘要
DESCRIPTION (provided by applicant): Systemic juvenile idiopathic arthritis (SJIA) is a rheumatic condition characterized by arthritis, quotidian fever, evanescent rash, and sometimes other types of systemic inflammation. SJIA is currently thought to be a multigenic, autoinflammatory disease, but the molecular details of its pathogenesis are still unknown. A striking feature of SJIA is its association with macrophage activation syndrome (MAS), a complication that can be fatal. This clinical aspect, together with data from immunophenotypic studies of SJIA, points to the monocyte lineage as being important in disease pathogenesis. Activated monocytes express components of the inflammasome, a multiprotein complex that senses infectious or noxious stimuli and activates caspase-1, leading to maturation and secretion of IL-1beta and IL-18 and sometimes to host cell death IL-1beta and IL-18 have been implicated in SJIA. Based on our preliminary data, we hypothesize that monocytes from SJIA patients harbor a defect in the inflammasome pathway. The objective of this R21 proposal is to discover host pathways and genes that influence IL- 1beta maturation and release by monocytes and to test these as candidate disease associated factors. In Aim 1, we will take a candidate approach to characterize possible defects in SJIA monocytes by measuring known molecular events related to IL-1beta secretion in cells from SJIA patients compared to cells from age-matched immunologically normal children. Specifically, we will measure cytokine release, activation of caspase-1, caspase-1 regulated cell death, levels of expression of Rab 39a, the purinergic receptor P2X7R, and the pore-forming protein, pannexin-1. Findings will be followed up with sequencing of associated candidate genes in 35 SJIA patients. In Aim 2, we will take a less biased approach and conduct a forward genetic screen to identify host factors that influence IL-1beta secretion in normal cells. This screen will likely provide additional candidate factors potentially affecting IL-1beta biology in SJIA. Our results will delineate molecular components regulating IL-1 processing and secretion and, ultimately, could result in new and innovative approaches to the prevention and treatment of SJIA and other autoinflammatory diseases.
PUBLIC HEALTH RELEVANCE: Systemic juvenile idiopathic arthritis (sJIA) is a chronic rheumatic condition in children characterized by remitting fever, transient rash, and relapsing arthritis. Although sJIA represents only 10-20% of the total cases of chronic inflammatory arthritis in children (JIA), it accounts for more than 2/3 of JIA mortality, due to complications o this disease and its treatment. The cause of sJIA is unknown, but recent evidence strongly suggests that a driving force is excessive activity of an endogenous inflammatory mediator called IL-1. This conclusion is based on the efficacy of anti-IL-1 therapy in a large subset of sJI patients, especially if this treatment approach is instituted early. We are interested in elucidatig the basis of uncontrolled IL-1 activity in sJIA. The Mellins laboratory has been studying the immune cells found in the blood of children with sJIA and has found evidence for abnormal regulation of IL-1 secretion in these cells. The Monack laboratory has been studying the basic cellular mechanisms that control IL-1 secretion in immune cells. While certain aspects of IL-1 control have been uncovered, such as the importance of a subcellular structure known as the "inflammasome," it is clear that more molecular events remain to be discovered. Using modern genetic and biochemical approaches, our laboratories will work to identify the molecular steps involved in production and secretion of active IL-1 from immune cells. We then will go on to determine at which step(s) the immune cells from sJIA patients are abnormal. This project will contribute important new knowledge on the fundamental processes involved in inflammation and will shed light on the mechanism of disease in a chronic, sometimes fatal illness of children, sJIA. The project also has the potential to identify approaches to treatments for sJIA and other inflammatory diseases where IL-1 plays a pathogenic role.
描述(由申请人提供):系统性幼年特发性关节炎(SJIA)是一种风湿性疾病,其特征为关节炎、日常发热、消退性皮疹,有时还有其他类型的全身炎症。目前认为 SJIA 是一种多基因自身炎症性疾病,但其发病机制的分子细节仍不清楚。 SJIA 的一个显着特征是它与巨噬细胞激活综合征 (MAS) 相关,这是一种可能致命的并发症。这一临床方面以及 SJIA 免疫表型研究的数据表明单核细胞谱系在疾病发病机制中发挥着重要作用。激活的单核细胞表达炎症小体的成分,炎症小体是一种多蛋白复合物,可感知传染性或有害刺激并激活 caspase-1,导致 IL-1β 和 IL-18 的成熟和分泌,有时导致宿主细胞死亡。IL-1β 和 IL-18 与 SJIA 有关。根据我们的初步数据,我们假设 SJIA 患者的单核细胞存在炎性体途径缺陷。该 R21 提案的目的是发现影响单核细胞 IL-1β 成熟和释放的宿主途径和基因,并将这些作为候选疾病相关因素进行测试。在目标 1 中,我们将采用一种候选方法,通过测量 SJIA 患者细胞与年龄匹配的免疫正常儿童细胞中与 IL-1beta 分泌相关的已知分子事件,来表征 SJIA 单核细胞可能存在的缺陷。具体来说,我们将测量细胞因子释放、caspase-1 激活、caspase-1 调节的细胞死亡、Rab 39a、嘌呤受体 P2X7R 和成孔蛋白 pannexin-1 的表达水平。研究结果将通过对 35 名 SJIA 患者的相关候选基因进行测序来跟进。在目标 2 中,我们将采取较少偏见的方法并进行正向遗传筛选,以确定影响正常细胞中 IL-1beta 分泌的宿主因素。该筛选可能会提供可能影响 SJIA 中 IL-1beta 生物学的其他候选因素。我们的研究结果将描述调节 IL-1 加工和分泌的分子成分,并最终可能产生预防和治疗 SJIA 和其他自身炎症性疾病的创新方法。
公众健康相关性:系统性幼年特发性关节炎 (sJIA) 是一种儿童慢性风湿性疾病,其特征为缓解发热、短暂性皮疹和复发性关节炎。尽管 sJIA 仅占儿童慢性炎症性关节炎 (JIA) 病例总数的 10-20%,但由于该疾病及其治疗的并发症,它占 JIA 死亡率的 2/3 以上。 sJIA 的病因尚不清楚,但最近的证据强烈表明驱动力是一种称为 IL-1 的内源性炎症介质的过度活性。这一结论是基于抗 IL-1 治疗对大部分 sJI 患者的疗效,特别是如果尽早开始这种治疗方法。我们有兴趣阐明 sJIA 中不受控制的 IL-1 活性的基础。梅林斯实验室一直在研究 sJIA 儿童血液中的免疫细胞,并发现这些细胞中 IL-1 分泌调节异常的证据。 Monack 实验室一直在研究控制免疫细胞中 IL-1 分泌的基本细胞机制。虽然IL-1控制的某些方面已经被揭示,例如被称为“炎性体”的亚细胞结构的重要性,但显然还有更多的分子事件有待发现。我们的实验室将利用现代遗传和生化方法,努力确定免疫细胞产生和分泌活性 IL-1 所涉及的分子步骤。然后我们将继续确定 sJIA 患者的免疫细胞在哪一步出现异常。该项目将贡献有关炎症基本过程的重要新知识,并将揭示儿童慢性、有时甚至致命的幼年特发性关节炎的发病机制。该项目还有可能找到治疗 sJIA 和其他由 IL-1 致病的炎症性疾病的方法。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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Elizabeth D Mellins其他文献
Systemic juvenile idiopathic arthritis is associated with HLA-DRB1 in Europeans and Americans of European descent
- DOI:
10.1186/1546-0096-10-s1-a6 - 发表时间:
2012-07-13 - 期刊:
- 影响因子:2.300
- 作者:
Michael Ombrello;Elaine F Remmers;Alexei A Grom;Wendy Thomson;Alberto Martini;Marco Gattorno;Seza Ozen;Ahmet Gul;John F Bohnsack;Andrew S Zeft;Elizabeth D Mellins;Jane L Park;Claudio Len;Colleen Satorius;Ricardo AG Russo;Terri H Finkel;Rae SM Yeung;Rayfel Schneider;Sampath Prahalad;David N Glass;Roger C Allen;Nico Wulffraat;Pierre Quartier;Maria Odete E Hilario;Kevin Murray;Sheila Oliveira;Jordi Anton;Anne Hinks;Eleftheria Zeggini;Carl Langefeld;Susan Thompson;Jeffrey Chaitow;Justine Ellis;Davinder Singh;Andre Cavalvanti;Blanca Bica;Flavio Sztajnbok;Hakon Hakonarson;Katherine A Siminovitch;Kirsten Minden;Peter Haas;Tobias Schwarz;Daniel L Kastner;Patricia Woo - 通讯作者:
Patricia Woo
Demographic, clinical and treatment characteristics of the carra registry systemic JIA cohort
- DOI:
10.1186/1546-0096-12-s1-p64 - 发表时间:
2014-09-17 - 期刊:
- 影响因子:2.300
- 作者:
Ginger Janow;Laura Schanberg;Soko Setoguchi;Elizabeth D Mellins;Rayfel Schneider;Yukiko Kimura - 通讯作者:
Yukiko Kimura
Elizabeth D Mellins的其他文献
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{{ truncateString('Elizabeth D Mellins', 18)}}的其他基金
Immunoglobulin as a novel ligand for HLA-DM
免疫球蛋白作为 HLA-DM 的新型配体
- 批准号:
8177239 - 财政年份:2011
- 资助金额:
$ 21.33万 - 项目类别:
Immunoglobulin as a novel ligand for HLA-DM
免疫球蛋白作为 HLA-DM 的新型配体
- 批准号:
8264930 - 财政年份:2011
- 资助金额:
$ 21.33万 - 项目类别:
A role for IL-1 in SJIA monocyte phenotypes: A RAPPORT ancillary study
IL-1 在 SJIA 单核细胞表型中的作用:一项 RAPPORT 辅助研究
- 批准号:
8325175 - 财政年份:2010
- 资助金额:
$ 21.33万 - 项目类别:
A role for IL-1 in SJIA monocyte phenotypes: A RAPPORT ancillary study
IL-1 在 SJIA 单核细胞表型中的作用:一项 RAPPORT 辅助研究
- 批准号:
8146977 - 财政年份:2010
- 资助金额:
$ 21.33万 - 项目类别:
A role for IL-1 in SJIA monocyte phenotypes: A RAPPORT ancillary study
IL-1 在 SJIA 单核细胞表型中的作用:一项 RAPPORT 辅助研究
- 批准号:
8530018 - 财政年份:2010
- 资助金额:
$ 21.33万 - 项目类别:
A role for IL-1 in SJIA monocyte phenotypes: A RAPPORT ancillary study
IL-1 在 SJIA 单核细胞表型中的作用:一项 RAPPORT 辅助研究
- 批准号:
8088935 - 财政年份:2010
- 资助金额:
$ 21.33万 - 项目类别:
Protective Mechanisms Against Pandemic Respiratory Virus (Resource D)
针对流行性呼吸道病毒的保护机制(资源 D)
- 批准号:
7657181 - 财政年份:2008
- 资助金额:
$ 21.33万 - 项目类别:
Mechanism of MHC Association with Type 1 Diabetes
MHC与1型糖尿病的关联机制
- 批准号:
7479078 - 财政年份:2008
- 资助金额:
$ 21.33万 - 项目类别: