Inflammasome adaptor and effectors in Cryopyrinopathies and crystal arthropathies

描述(申请人提供)：炎性小体是促进促炎症细胞因子白介素1和白介素18成熟和分泌的蛋白质复合体，白介素1和白介素18对先天免疫反应很重要。然而，为了维持动态平衡和暂时的炎症，激活小体是必不可少的，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症性疾病有关。炎症体激活的第一步是通过模式识别受体(PRRs)感知病原体和细胞危险信号，含有吡咯环结构域的NOD样受体(NLRP)3就是其中之一。一旦激活，NLRP3就会招募接头ASC和效应器caspase-1，后者随后将IL-1？和IL-18处理成具有生物活性的形式。然而，最近有人提出线粒体MAVS蛋白也可以作为炎症体适配器，并且caspase-11和-8被认为是细菌感染过程中NLRP3炎症体的替代效应因子。然而，它们在风湿性和炎症性疾病中对NLRP3炎症体激活的作用和相关性还没有被研究。NLRP3的正常功能对人类健康至关重要，因为NLRP3炎症小体调节的缺陷与几种炎症性疾病有关，包括冰冻疾病和晶体关节病。虽然遗传突变使NLRP3在冰冻疾病中具有结构性活性，但在关节中以尿酸单钠(MSU)晶体形式沉淀的过量危险信号会触发NLRP3炎症体激活和急性局部炎症反应，从而导致痛风性关节炎。因此，在这两种疾病中，NLRP3的不受控制的激活导致IL-1ç的过度产生。因此，阻断IL-1ç可改善疾病症状和患者预后。然而，IL-1？对于先天免疫反应是至关重要的，完全消除IL-1？也会削弱宿主防御。因此，深入了解NLRP3炎性小体在冰冻肾炎和晶体关节病中的调控，对于开发特异性的NLRP3炎性小体靶向治疗是至关重要的。本研究拟利用小鼠体内模型，研究MAVS和caspase-11、-8在NLRP3炎症性连锁Muckle-Wells综合征(MWS)和MSU晶体诱导痛风中的作用。我预计这项研究的结果将对未来MWS和痛风的治疗以及其他NLRP3相关疾病的治疗具有广泛的影响，同时将有助于更好地理解NLRP3炎症体生物学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生的免疫学机制。我相信这项提议是K01指导科学家发展奖的理想培训工具，因为我将精通风湿性和炎症性疾病的小鼠模型，以及翻译免疫学，从而在我开始建立独立的学术生涯时发展自己的利基市场。

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.