Inflammasome adaptor and effectors in Cryopyrinopathies and crystal arthropathies

描述（由申请人提供）：炎性小体是促进促炎细胞因子白介素(IL) -1 β和IL-18成熟和分泌的蛋白质复合物，它们对先天免疫反应很重要。然而，维持体内平衡和暂时的炎性体激活是必不可少的，因为不受控制和过度的细胞因子产生与风湿病和其他炎症性疾病有关。炎性小体激活的第一步是模式识别受体（PRRs）对病原体和细胞危险信号的感知，而含有pyrin结构域的nod样受体（NLRP） 3就是其中之一。激活后，NLRP3招募接头ASC和效应caspase-1，随后将IL-1ß和IL-18加工成其生物活性形式。然而，最近有人提出线粒体MAVS蛋白也可以作为炎症小体的接头，并且在细菌感染期间，caspase -11和-8被认为是NLRP3炎症小体的替代效应物。然而，它们在风湿病和炎症性疾病中与NLRP3炎性体激活的作用和相关性尚未被研究。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，包括冻疮病和晶体关节病。虽然遗传突变使NLRP3在冻疮病中具有组成性活性，但关节中尿酸钠（MSU）晶体沉淀物形式的过量危险信号会触发NLRP3炎性体激活和急性局部炎症反应，导致痛风性关节炎。因此，在这两种疾病中，NLRP3不受控制的激活导致过量的IL-1ß产生。因此，阻断IL-1ß可改善疾病症状和患者预后。然而，IL-1ß对先天免疫反应至关重要，完全消除IL-1ß也会损害宿主的防御。因此，详细了解NLRP3炎性小体在冻疮病和晶体关节病中的调控，以开发特异性的NLRP3炎性小体靶向治疗是至关重要的。我建议利用小鼠体内模型研究MAVS和caspase -11和-8在NLRP3炎性体相关的Muckle-Wells综合征（MWS）（一种低温病）和MSU晶体诱导的痛风中的作用。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NLRP3相关疾病的治疗产生广泛的影响，并同时有助于更好地理解NLRP3炎症小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。我相信这个提案是K01指导科学家发展奖的理想培训工具，因为我将熟练掌握风湿性和炎症性疾病的小鼠模型，以及转化免疫学，从而在我开始建立独立的学术生涯时发展自己的利基。

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.