Molecular etiology of familial Mediterranean fever

家族性地中海热的分子病因学

• 批准号: 7162083
• 负责人: DEBORAH L. GUMUCIO
• 金额: $ 34.38万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7162083
• 关键词: Abdomen; Accounting; Actins; Acute; Acute-Phase Proteins; Acute-Phase Reaction; Affect; Alleles; Amyloidosis; Apoptosis; Apoptotic; Arthritis; Biological Assay; Blood Vessels; Cell Nucleus; Cell physiology; Cells; Cessation of life; Chest; Chronic; Complication; Cutaneous; Cytoskeleton; Data; Death Domain; Dendritic Cells; Disease; Erythema; Ethnic group; Etiology; Evolution; Exons; Familial Mediterranean Fever; Family member; Fever; Fibroblasts; Frequencies; Hereditary Periodic Fever Syndromes; Heterozygote; Human; Immune system; Infection due to Erysipelothrix rhusiopathiae (disorder); Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Joints; Life; Link; Localized; Membrane; Missense Mutation; Modeling; Molecular; Mutation; Myalgia; Myocardium; Natural Immunity; Neonatal; Neurologic; Organ; PAPA syndrome; Pain; Pathogenesis; Pathway interactions; Patients; Pattern; Pericarditis; Peritoneal; Peritonitis; Pleural; Pleurisy; Primates; Production; Protein Family; Protein Isoforms; Proteins; RNA Splicing; Recurrence; Role; Signal Transduction; Site; Skin; Skin Manifestations; Structure; Syndrome; Synovial Cell; Testing; Upper arm; Urticaria; Vasculitis; Work; Yeasts; cell type; cytokine; day; design; eosinophil; human disease; immune function; infancy; marenostrin; monocyte; mutant; neutrophil; pathogen; research study; response; yeast two hybrid system

Patients with the autosomal recessive disease, Familial Mediterranean fever (FMF), suffer periodic, upredictable attacks of fever associated with severe pain; the pain is localized most commonly in joints (arthritis), abdomen (peritonitis) or chest (pleuritis). Occasionally, this disease presents with skin manifestations (erysipeloid erythema), pericarditis, vasculitis, or myalgia. In many patients, amyloidosis is a complication, and if untreated, this can be life-threatening. FMF is caused by missense mutations in pyrin, a protein of unknown function expressed in neutrophils, monocytes, eosinophils, dendritic cells, synovial cells and skin and peritoneal fibroblasts. Pyrin expression in these cells is induced by pro-inflammatory cytokines and by LPS. Thus, it has been speculated that pyrin modulates the inflammatory response. Evolutionary studies of the pyrin molecule indicate that it has been under positive Darwinian selection during evolution of the primates. Moreover, the high frequency of mutant pyrin alleles in several human ethnic groups supports a heterozygote (selective) advantage for the mutant allele. Mutant forms of pyrin may enhance the body's ability to clear important pathogen(s). Indeed, acute phase reactants, important agents of innate immunity, are up-regulated not only in patients but in carriers of mutant alleles. Structural analysis of the pyrin molecule revealed that exon 1 encodes a death-domain related structural motif (known as the pyrin domain or PyD) that is found in a growing family of proteins involved in inflammation and innate immunity. Identification of pyrin-interacting proteins as well as additional functional studies reveal that pyrin is linked directly to apoptotic and cytoskeletal signaling cascades, and that it modulates cytokine secretion. Experiments described in this proposal are designed to further explore these functions of pyrin and determine the effects of pyrin mutations on apoptosis (Aim 1); cytoskeletal signaling (Aim 2); and cytokine production (Aim 3). Recently identified pyrin isoforms will also be examined in these functional assays, since preliminary studies indicate that the various isoforms may function differently. Such studies could provide clues to understanding of the molecular pathogenesis of FMF, and may reveal new information about inflammatory pathways in general. In fact, pyrin-interacting proteins and pyrin domain-containing family members have already been connected to several human diseases, including inflammatory bowel disease, PAPA syndrome, Muckle-Wells sydrome, familial cold urticaria, Blau syndrome and Be_het's disease.

患有常染色体隐性遗传疾病、家族性地中海热 (FMF) 的患者会遭受周期性、 不可预测的发烧并伴有剧烈疼痛；疼痛最常见于关节 （关节炎）、腹部（腹膜炎）或胸部（胸膜炎）。有时，这种疾病会出现在皮肤上 表现（丹毒样红斑）、心包炎、血管炎或肌痛。在许多患者中，淀粉样变性是一种 并发症，如果不及时治疗，可能会危及生命。 FMF 是由pyrin 的错义突变引起的，pyrin 是一种 在中性粒细胞、单核细胞、嗜酸性粒细胞、树突状细胞、滑膜细胞中表达的功能未知的蛋白质 以及皮肤和腹膜成纤维细胞。这些细胞中的 Pyrin 表达是由促炎细胞因子诱导的 和LPS。因此，推测吡啶调节炎症反应。进化论 对吡啶分子的研究表明，它在进化过程中一直处于达尔文正选择之下。 灵长类动物。此外，在几个人类种族中，突变的pyrin等位基因的高频率支持了 突变等位基因的杂合子（选择性）优势。吡啶的突变形式可能会增强身体的 清除重要病原体的能力。事实上，急性期反应物是先天免疫的重要因素， 不仅在患者中上调，而且在突变等位基因的携带者中也上调。吡啶分子的结构分析 揭示外显子 1 编码一个死亡结构域相关的结构基序（称为pyrin结构域或PyD）， 存在于越来越多的涉及炎症和先天免疫的蛋白质家族中。鉴定 吡啶相互作用蛋白以及其他功能研究表明，吡啶直接与 细胞凋亡和细胞骨架信号级联反应，并调节细胞因子的分泌。实验 该提案中描述的目的是进一步探索吡啶的这些功能并确定 Pyrin 突变对细胞凋亡的影响（目标 1）；细胞骨架信号传导（目标 2）；和细胞因子的产生（目标 3）。 最近鉴定的吡啶异构体也将在这些功能测定中进行检查，因为初步研究 表明不同的亚型可能具有不同的功能。此类研究可以提供线索 了解 FMF 的分子发病机制，并可能揭示有关炎症的新信息 一般的途径。事实上，pyrin 相互作用蛋白和包含pyrin 结构域的家族成员 已经与多种人类疾病有关，包括炎症性肠病、PAPA 综合征、 Muckle-Wells 综合征、家族性寒冷性荨麻疹、Blau 综合征和 Be_thet 病。

项目成果

Familial Mediterranean fever in the post-genomic era: how an ancient disease is providing new insights into inflammatory pathways.

后基因组时代的家族性地中海热：一种古老的疾病如何为炎症途径提供新的见解。

• 发表时间: 2005-02
• 作者: Schaner, Philip E;Gumucio, Deborah L
• 通讯作者: Gumucio, Deborah L

Pyrin and ASC co-localize to cellular sites that are rich in polymerizing actin.

Pyrin 和 ASC 共定位于富含聚合肌动蛋白的细胞位点。

• 发表时间: 2009-01
• 作者: Waite, Andrea L;Schaner, Philip;Hu, Chunbo;Richards, Neil;Balci;Hong, Arthur;Fox, Michelle;Gumucio, Deborah L
• 通讯作者: Gumucio, Deborah L

Expression of ASC in renal tissues of familial mediterranean fever patients with amyloidosis: postulating a role for ASC in AA type amyloid deposition.

家族性地中海热淀粉样变性患者肾组织中 ASC 的表达：推测 ASC 在 AA 型淀粉样蛋白沉积中的作用。

• 发表时间: 2008-11
• 作者: Balci;Waite, Andrea L;Schaner, Philip;Taskiran, Zihni Ekim;Richards, Neil;Orhan, Diclehan;Gucer, Safak;Ozen, Seza;Gumucio, Deborah;Yilmaz, Engin
• 通讯作者: Yilmaz, Engin

Pyrin, product of the MEFV locus, interacts with the proapoptotic protein, Siva.

Pyrin 是 MEFV 基因座的产物，与促凋亡蛋白 Siva 相互作用。

• 发表时间: 2008-09
• 影响因子: 5.6
• 作者: Balci;Waite, Andrea L;Hu, Chunbo;Richards, Neil;Staubach;Yilmaz, Engin;Gumucio, Deborah L
• 通讯作者: Gumucio, Deborah L

Pyrin Modulates the Intracellular Distribution of PSTPIP1.

Pyrin 调节 PSTPIP1 的细胞内分布。

• 发表时间: 2009-07-07
• 影响因子: 3.7
• 作者: Waite, Andrea L;Schaner, Philip;Richards, Neil;Balci;Masters, Seth L;Brydges, Susannah D;Fox, Michelle;Hong, Arthur;Yilmaz, Engin;Kastner, Daniel L;Reinherz, Ellis L;Gumucio, Deborah L
• 通讯作者: Gumucio, Deborah L