Inflammasome adaptor and effectors in Cryopyrinopathies and crystal arthropathies

冷热蛋白病和晶体关节病中的炎性小体接头和效应器

• 批准号: 8891653
• 负责人: Andrea Dorfleutner
• 金额: $ 11.57万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8891653
• 关键词: Adaptor Signaling Protein; Anti-Inflammatory Agents; Anti-inflammatory; Antiviral Agents; Apoptosis; Area; Arthritis; Award; Bacterial Infections; Belief; Biological Assay; Biology; Bone Marrow; Caspase; Caspase-1; Cell Death; Cell Line; Complex; Defect; Development; Disease; Equilibrium; Excision; Familial amyloid nephropathy with urticaria and deafness; Flow Cytometry; Focus Groups; Future; Germ-Line Mutation; Goals; Gout; Gouty Arthritis; Health; Hereditary Disease; Homeostasis; Host Defense; Human; Immune response; Immunologics; Immunology; In Vitro; Inflammatory; Interleukin-1 beta; Interleukin-18; Interleukins; Joints; K-Series Research Career Programs; Knockout Mice; Knowledge; Link; Local Acute Inflammatory Response Pathway; Mediating; Mentors; Mitochondria; Molecular; Mus; Mutation; Myelogenous; Outcome; Pathogenesis; Pathology; Patients; Pattern recognition receptor; Pharmaceutical Preparations; Process; Production; Proteins; Recruitment Activity; Regulation; Relative (related person); Research; Research Personnel; Role; Scientist; Signal Transduction; Signaling Protein; Symptoms; Techniques; Time; Training; Urate; Work; arthropathies; base; career; caspase-8; cytokine; immune clearance; improved; in vivo; macrophage; marenostrin; mouse model; novel; novel strategies; pathogen; protein complex; receptor; targeted treatment; therapeutic target; translational medicine; translational study

DESCRIPTION (provided by applicant): Inflammasomes are protein complexes that facilitate the maturation and secretion of the pro-inflammatory cytokines interleukin (IL) -1ß and IL-18, which are important for innate immune responses. Nevertheless, for maintaining homeostasis balance and temporary inflammasome activation is essential, since uncontrolled and excessive cytokine production has been linked to rheumatic and other inflammatory diseases. The first step of inflammasome activation is the sensing of pathogens and cellular danger signals by pattern recognition receptors (PRRs) and the NOD-like receptor containing a pyrin domain (NLRP) 3 is one of them. Upon activation, NLRP3 recruits the adaptor ASC and the effector caspase-1, which subsequently processes IL-1ß and IL-18 into their biologically active forms. However, recently the mitochondrial MAVS protein has been proposed to also function as an inflammasome adaptor and caspases-11 and -8 were implicated as alternative effectors for NLRP3 inflammasomes during bacterial infections. Nevertheless, their contribution and relevance to NLRP3 inflammasome activation in rheumatic and inflammatory diseases has not been investigated yet. The proper function of NLRP3 is crucial for human health, since defects in the NLRP3 inflammasome regulation are associated with several inflammatory diseases, including Cryopyrinopathies and crystal arthropathies. While hereditary mutations render NLRP3 constitutively active in Cryopyrinopathies, an excess of danger signals in the form of monosodium urate (MSU) crystal precipitates in the joint triggers NLRP3 inflammasome activation and an acute local inflammatory response that causes gouty arthritis. Hence, in both diseases the uncontrolled activation of NLRP3 leads to excessive IL-1ß production. Consequently, blocking IL-1ß improves disease symptoms and patient outcomes. However, IL-1ß is crucial for innate immune responses and elimination of IL-1ß altogether can also impair host defense. Thus, it is crucial to gain a detailed understanding of the NLRP3 inflammasomes regulation in Cryopyrinopathies and crystal arthropathies in order to develop specific NLRP3 inflammasome targeted therapies. I propose to study the function of MAVS and caspases-11 and -8 in NLRP3 inflammasome linked Muckle-Wells syndrome (MWS), which is a Cryopyrinopathy, and MSU crystal-induced gout by utilizing in vivo mouse models. I expect that the results from this study will have widespread implications for future therapies of MWS and gout but also for other NLRP3-associated diseases and will concurrently contribute to a better understanding of the complex molecular mechanisms involved in NLRP3 inflammasome biology. My long-term career goal is to build an academic research group focused on understanding immunologic mechanisms underlying the development of rheumatic and inflammatory diseases. I belief that this proposal is an ideal training vehicle for a K01 Mentored Scientist Development Award, as I will become proficient in mouse models of rheumatic and inflammatory diseases, as well as translational immunology, thereby developing my own niche as I begin to establish an independent academic career.

描述（由申请人提供）：炎性小体是促进促炎细胞因子白细胞介素（IL）-1 β和IL-18成熟和分泌的蛋白质复合物，这些细胞因子对先天免疫应答很重要。然而，为了维持稳态平衡和暂时的炎性体激活是必不可少的，因为不受控制的和过度的细胞因子产生与风湿性和其他炎性疾病有关。炎性小体激活的第一步是通过模式识别受体（PRR）感测病原体和细胞危险信号，并且含有pyrin结构域的NOD样受体（NLRP）3是其中之一。在活化后，NLRP 3募集衔接子ASC和效应子胱天蛋白酶-1，其随后将IL-10和IL-18加工成其生物活性形式。然而，最近已经提出线粒体MAVS蛋白也作为炎性体衔接子起作用，并且半胱天冬酶-11和半胱天冬酶-8被认为是细菌感染期间NLRP 3炎性体的替代效应物。然而，它们在风湿性和炎性疾病中对NLRP 3炎性小体活化的贡献和相关性尚未研究。NLRP 3的适当功能对于人类健康至关重要，因为NLRP 3炎性体调节的缺陷与几种炎性疾病相关，包括Cryopyrinopathies和crystalarthropathies。虽然遗传性突变使NLRP 3在Cryopyrin病中具有组成性活性，但关节中以尿酸盐（MSU）晶体沉淀物形式的过量危险信号触发NLRP 3炎性小体活化和引起痛风性关节炎的急性局部炎症反应。因此，在这两种疾病中，NLRP 3的不受控制的激活导致过量的IL-1 β产生。因此，阻断IL-1 β可改善疾病症状和患者预后。然而，IL-1 β对先天免疫应答至关重要，完全消除IL-1 β也会损害宿主防御。因此，为了开发特异性NLRP 3炎性小体靶向疗法，获得对Cryopyrinopathies和晶体关节病中NLRP 3炎性小体调节的详细理解是至关重要的。我建议通过利用体内小鼠模型来研究MAVS和半胱天冬酶-11和-8在NLRP 3炎性小体相关的Muckle-Wells综合征（MWS）（一种Cryopyrinopathy）和MSU晶体诱导的痛风中的功能。我希望这项研究的结果将对未来MWS和痛风的治疗以及其他NLRP 3相关疾病产生广泛的影响，并同时有助于更好地理解NLRP 3炎性体生物学中涉及的复杂分子机制。我的长期职业目标是建立一个学术研究小组，专注于了解风湿性和炎症性疾病发展的免疫机制。我相信，这个建议是一个理想的培训工具K 01指导科学家发展奖，因为我将成为精通风湿性和炎症性疾病的小鼠模型，以及转化免疫学，从而发展我自己的利基，因为我开始建立一个独立的学术生涯。