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.

家族性地中海热（FMF）常染色体隐性遗传病患者出现周期性、

项目成果

Pyrin Modulates the Intracellular Distribution of PSTPIP1.

• DOI: 10.1371/journal.pone.0006147
• 发表时间: 2009-07-07
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Waite AL;Schaner P;Richards N;Balci-Peynircioglu B;Masters SL;Brydges SD;Fox M;Hong A;Yilmaz E;Kastner DL;Reinherz EL;Gumucio DL
• 通讯作者: Gumucio DL

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。

• DOI: 10.2174/1568010053622803
• 发表时间: 2005
• 期刊: Current drug targets. Inflammation and allergy
• 作者: Schaner,PhilipE;Gumucio,DeborahL
• 通讯作者: Gumucio,DeborahL