Inflammasome function and SJIA

炎症小体功能和 SJIA

• 批准号: 8513260
• 负责人: Elizabeth D Mellins
• 金额: $ 16.89万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/8513260
• 关键词: Accounting; Adaptor Signaling Protein; Affect; Age; Apoptosis; Arthritis; Biochemical; Biology; Blood; C-reactive protein; Candidate Disease Gene; Caspase-1; Cell Aging; Cell Death; Cells; Child; Chronic; Chronic Childhood Arthritis; Cleaved cell; Clinical; Complex; Complication; Data; Defect; Disease; Employee Strikes; Evaluation; Event; Exanthema; Fever; Genes; Genetic; Genetic Screening; Goals; Hereditary Disease; Immune; Inflammation; Inflammation Mediators; Inflammatory; Institutes; Integration Host Factors; Interleukin-1; Interleukin-18; Knowledge; Laboratories; Lead; Light; Macrophage Activation; Measures; Mediating; Molecular; Multiprotein Complexes; Mutation; Normal Cell; Pathogenesis; Pathway interactions; Patients; Peptide Signal Sequences; Pericarditis; Play; Pleurisy; Prevention approach; Process; Production; Proteins; Purinoceptor; Regulation; Relapse; Resolution; Rheumatoid Arthritis; Role; Small Interfering RNA; Staging; Stimulus; Subcellular structure; Syndrome; Testing; Work; anakinra; arthritis therapy; base; cell age; cytokine; driving force; follow-up; genome-wide; inhibitor/antagonist; innovation; interest; macrophage; monocyte; mortality; novel; porin; response; secretion process

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.

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，其特征是关节炎、日常发热、短暂皮疹，有时还会出现其他类型的全身性炎症。目前认为SJIA是一种多基因的自身炎症性疾病，但其发病机制的分子细节尚不清楚。SJIA的一个显著特征是它与巨噬细胞激活综合征（MAS）有关，这是一种可能致命的并发症。这一临床方面，加上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起重要作用。活化的单核细胞表达炎性小体的成分，炎性小体是一种多蛋白复合物，可感知感染性或有害刺激并激活caspase-1，导致il -1 β和IL-18的成熟和分泌，有时导致宿主细胞死亡il -1 β和IL-18与SJIA有关。根据我们的初步数据，我们假设来自SJIA患者的单核细胞在炎性小体通路中存在缺陷。本R21提案的目的是发现影响IL- 1 β成熟和单核细胞释放的宿主途径和基因，并将其作为候选疾病相关因素进行测试。在Aim 1中，我们将采用一种候选方法，通过测量与年龄匹配的免疫正常儿童细胞相比，SJIA患者细胞中il -1 β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的激活、caspase-1调节的细胞死亡、Rab 39a、嘌呤能受体P2X7R和成孔蛋白pannexin-1的表达水平。研究人员将对35例SJIA患者的相关候选基因进行测序。在Aim 2中，我们将采用较少偏见的方法，进行正向遗传筛选，以确定影响正常细胞中il -1 β分泌的宿主因素。该筛选可能会提供潜在影响SJIA il -1 β生物学的其他候选因子。我们的研究结果将描述调节IL-1加工和分泌的分子成分，最终可能导致新的和创新的方法来预防和治疗SJIA和其他自身炎症性疾病。