The Role of Cryopyrin in Autoinflammatory Diseases

Cryopyrin 在自身炎症性疾病中的作用

• 批准号: 8121470
• 负责人: HAROLD M HOFFMAN
• 金额: $ 37.14万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8121470
• 关键词: Allergic; Alternative Splicing; Attention; Autoimmune Process; Binding; Cell Line; Cells; Development; Disease; Family; Genes; Goals; Gout; Health; Human; Immune response; Immune system; Immunologic Receptors; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Inherited; Interleukin-1; Lead; Leucine-Rich Repeat; Ligands; Mediating; Modeling; Molecular; Mus; Mutate; Mutation; Natural Immunity; Nucleotides; Pathway interactions; Patients; Pattern; Play; Process; Protein Isoforms; Proteins; Resistance to infection; Rheumatoid Arthritis; Role; Signal Transduction; Specificity; Stimulus; Study models; Syndrome; Toll-like receptors; cytokine; effective therapy; improved; in vivo; insight; macrophage; monocyte; mouse model; novel; pathogen; protein function; response

DESCRIPTION (provided by applicant): Inflammation is fundamentally a protective mechanism; however, in allergic, autoimmune, and autoinflammatory disorders, alterations in the inflammatory processes result in disease. Inflammation can be initiated by such varied stimuli as pathogens and generalized cold exposure, and the innate immune system plays a role in these responses. Although recently the focus of intense study, the innate immune system is not well characterized. Familial cold autoinflammatory syndrome (FCAS) is an excellent model for the study of innate immunity and the immune system's response to physical stimuli. Study of the molecular mechanisms of FCAS has led to novel effective cytokine targeted therapies for the disorder. The mutated gene (CIAS1) and protein (cryopyrin) identified in FCAS may play an important role in more common inflammatory disorders such as rheumatoid arthritis and gout. Our identification of CIAS1 and cryopyrin has brought attention to a new family of intracellular innate immune receptors known as Nucleotide binding domain-Leucine rich Repeats (NLRs) that share common features with Toll-like receptors which are integral in innate immune response. Cryopyrin's role in innate immunity is under study, and cryopyrin has been shown to sense a variety of exogenous and endogenous danger signals. Cryopyrin's extensive alternative splicing may be one mechanism in the innate immune system for creating specificity for multiple ligands. The main goal of this proposal is to delineate the processes through which cryopyrin mediates inflammation in response to cold and determine if this process is protective against pathogens. This will necessitate identification of the role of alternative splicing, especially as it relates to ligand specificity and protein function. The following lines of experimentation will be carried out: 1) In vitro and in vivo studies with both human and mouse models will be utilized to identify the molecular mechanisms through which cold mediates inflammatory responses; 2) Systematic studies of the host-pathogen response will be performed to determine the effects of FCAS-associated cryopyrin mutations on in vitro mouse and human monocyte/macrophage response and systemic in vivo mouse response; 3) Expression patterns, functionality, and ligand specificity of cryopyrin isoforms will be studied. Understanding the mechanisms of auto-inflammatory and innate immune responses will impact on human health for several reasons: 1) It will allow for the development of new targeted therapies for inflammatory conditions which currently have few effective treatments; 2) It may provide insights into a means to improve resistance to infection; 3) Understanding how a physical stimulus such as cold can trigger inflammation may lead to therapies that are protective against cold induced disorders.

描述（由申请人提供）：炎症从根本上来说是一种保护机制；然而，在过敏性、自身免疫性和自身炎症性疾病中，炎症过程的改变会导致疾病。炎症可以由病原体和全身寒冷暴露等多种刺激引起，而先天免疫系统在这些反应中发挥着作用。尽管先天免疫系统最近成为深入研究的焦点，但其特征尚未得到很好的表征。家族性寒冷自身炎症综合征（FCAS）是研究先天免疫和免疫系统对物理刺激的反应的优秀模型。对 FCAS 分子机制的研究为该疾病带来了新型有效的细胞因子靶向疗法。 FCAS 中发现的突变基因 (CIAS1) 和蛋白质 (cryopyrin) 可能在类风湿性关节炎和痛风等更常见的炎症性疾病中发挥重要作用。我们对 CIAS1 和 Cryopyrin 的鉴定引起了人们对一种新的细胞内先天免疫受体家族的关注，称为核苷酸结合域 - 富含亮氨酸重复序列 (NLR)，其与 Toll 样受体具有共同特征，而 Toll 样受体是先天免疫反应中不可或缺的一部分。冷热蛋白在先天免疫中的作用正在研究中，并且冷热蛋白已被证明可以感知多种外源性和内源性危险信号。 Cryopyrin 广泛的选择性剪接可能是先天免疫系统中产生多种配体特异性的一种机制。该提案的主要目标是描述冷热蛋白介导寒冷反应炎症的过程，并确定该过程是否具有针对病原体的保护作用。这将需要确定选择性剪接的作用，特别是因为它与配体特异性和蛋白质功能有关。将进行以下实验：1）利用人和小鼠模型的体外和体内研究来确定寒冷介导炎症反应的分子机制； 2）将进行宿主-病原体反应的系统研究，以确定FCAS相关冷吡蛋白突变对体外小鼠和人类单核细胞/巨噬细胞反应以及全身小鼠体内反应的影响； 3) 将研究冷吡蛋白亚型的表达模式、功能性和配体特异性。了解自身炎症和先天免疫反应的机制将对人类健康产生影响，原因如下：1）它将有助于开发针对目前几乎没有有效治疗方法的炎症性疾病的新靶向疗法； 2）它可能提供对提高感染抵抗力的方法的见解； 3) 了解寒冷等物理刺激如何引发炎症可能会导致针对寒冷引起的疾病的治疗。

项目成果

The infevers autoinflammatory mutation online registry: update with new genes and functions.

发烧者自身炎症突变在线登记：更新新基因和功能。

• 发表时间: 2008-06
• 影响因子: 3.9
• 作者: Milhavet, Florian;Cuisset, Laurence;Hoffman, Hal M;Slim, Rima;El;Aksentijevich, Ivona;Lesage, Suzanne;Waterham, Hans;Wise, Carol;Sarrauste de Menthiere, Cyril;Touitou, Isabelle
• 通讯作者: Touitou, Isabelle

Initial description of the human NLRP3 promoter.

人类 NLRP3 启动子的初步描述。

• 发表时间: 2008-12
• 影响因子: 5
• 作者: Anderson, J P;Mueller, J L;Misaghi, A;Anderson, S;Sivagnanam, M;Kolodner, R D;Hoffman, H M
• 通讯作者: Hoffman, H M

Prevention of cold-associated acute inflammation in familial cold autoinflammatory syndrome by interleukin-1 receptor antagonist.

白细胞介素-1受体拮抗剂预防家族性感冒自身炎症综合征中与感冒相关的急性炎症。

• 发表时间: 2004-11-13
• 作者: Hoffman, Hal M;Rosengren, Sanna;Boyle, David L;Cho, Jae Y;Nayar, Jyothi;Mueller, James L;Anderson, Justin P;Wanderer, Alan A;Firestein, Gary S
• 通讯作者: Firestein, Gary S

Constitutively activated NLRP3 inflammasome causes inflammation and abnormal skeletal development in mice.

组成型激活的 NLRP3 炎性体会导致小鼠炎症和骨骼发育异常。

• 发表时间: 2012
• 影响因子: 3.7
• 作者: Bonar, Sheri L;Brydges, Susannah D;Mueller, James L;McGeough, Matthew D;Pena, Carla;Chen, Debbie;Grimston, Susan K;Hickman;Ravindran, Soumya;McAlinden, Audrey;Novack, Deborah V;Kastner, Daniel L;Civitelli, Roberto;Hoffman, H
• 通讯作者: Hoffman, H

Hereditary immunologic disorders caused by pyrin and cryopyrin.

由pyrin和cryopyrin引起的遗传性免疫疾病。

• 发表时间: 2007-09
• 影响因子: 5.5
• 作者: Hoffman; Hal M
• 通讯作者: Hal M