Novel Synovial Role in Pathogenesis of Gout

滑膜在痛风发病机制中的新作用

基本信息

批准号：
9810080
负责人：
Robert A. Terkeltaub
金额：
$ 18.62万
依托单位：
VETERANS MEDICAL RESEARCH FDN/SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9810080
关键词：
ABCG2 gene ADAMTS Acute Age Amino Acid Sequence Databases Anabolism Area Arthritis Automobile Driving Biological Biological Markers Biology Candidate Disease Gene Cells Characteristics Chronic Clinical Crystal Formation Crystallization Custom DNA Sequence Data Defect Deposition Development Disease Drops Enzymes Extracellular Matrix Female Fibroblasts Flare Frequencies Generations Genetic study Genomic DNA Genomic Data Commons Genomics Glycoproteins Gout Gouty Arthritis Hip region structure Hyperuricemia Image Inflammation Inflammatory Inflammatory Response Integral Membrane Protein Interleukin-1 Interphalangeal joint of toe Joints Knock-out Knowledge Lead Light Lighting Link Lubricants Mediator of activation protein Metabolic Diseases Metabolism Minority Molecular Chaperones Morbidity - disease rate Mucin 1 protein Mucins Mutation Nature O-Glycans Biosynthesis Pathway Outcome Pain Palpable Parents Pathogenesis Pathway interactions Patients Peptide Hydrolases Phenotype Play Polysaccharides Process Proteomics Public Health Pump Quantitative Trait Loci Risk Role Sampling Serum Small Interfering RNA Specimen Susceptibility Gene Synovial Membrane Synovitis Testing Therapeutic Tissues Toes Transfection Urate Uric Acid Variant Work arthropathies cell behavior clinical phenotype enzyme pathway experimental study genetic approach genome wide association study glycoprotein biosynthesis glycoproteomics glycosylation high reward high risk inhibitor/antagonist joint injury knock-down lubricin member new therapeutic target novel novel marker novel strategies prevent proband purine metabolism response reverse genetics sialylation subcutaneous targeted biomarker urate transporter

项目摘要

Abstract Gout is a highly prevalent disease manifesting most commonly as acute, episodic synovitis that characteristically is excruciatingly painful. Gout continues to grow as a public health problem. The disorder is promoted by elevated body stores of uric acid, and the clinical phenotypes of arthritis are caused by inflammatory responses associated with articular deposits of urate crystals. However, gout develops in only a minority subset of hyperuricemic subjects. Moreover, clinical responses to deposited urate crystals are highly variable, including the frequency and extent of acute arthritis, and progression to palpable subcutaneous tophi, chronic arthritis, and erosive joint damage. There is unmet need to define new therapy targets and biomarkers for incident gout and progression to erosive joint disease. The rationale for this high risk/high reward application is that by clarifying major gaps in knowledge in these areas, the work will be paradigm-shifting, and potentially identify new targets to help prevent and limit gout-associated morbidity. Emerging findings, including from certain arthropathies other than gout, suggest that altered extracellular matrix O-linked glycoprotein components such as the mucin-type boundary lubricant lubricin, and active urate pumping into the joint by an unidentified transport mechanism play a role in development of gout. Our scientific premise is that, in synovial fibroblast lining cells (FLS), mechanistically linked alterations in lubricin and other mucin-type extracellular matrix O-glycoproteins and increased urate secretion are in a mechanistic lop that promotes “common gout”, and progression to chronic, destructive synovitis. We will use primarily a combined candidate gene and reverse genetics approach to analyze a highly unusual observation, specifically a case of gout as an “experiment of nature”. The proband, an otherwise healthy female without hyperuricemia, at age 22 had onset of destructive hip synovitis, and asymmetric acute gouty arthritis flares of small and intermediate joints with classic toe joint gout erosions, and gout definitively confirmed. Collective preliminary data for proband whole genomic DNA, and serum glycomics, proteomics, and glycoproteomics suggest dysregulation in biosynthesis of lubricin and other mucin-type O-glycoproteins that normally serve as constitutive inhibitors of inflammation. Gene candidates are highly enriched in the “reactome” of TMEM171, an incompletely characterized transmembrane molecule implicated in urate transport and recently defined as a gout susceptibility gene. Specifically, the TMEM171 reactome comprises over 20 molecules involved in glycoprotein biosynthesis, more than 10 mucintype. O-glycoproteins, and over 20 ADAMTS protease superfamily members. The work aims to illuminate novel intersections between synovial extracellular matrix biology, urate metabolism and transport, tophus formation, and synovitis. Positive impact includes building a new disease paradigm for “common gout”, potential new biomarkers, and possible gout therapeutics from the novel class of O-glycoprotein agents.

抽象的痛风是一种高度可行的疾病，最常表现为急性，发作的滑膜炎，痛苦的痛苦是痛苦的。由尿酸的身体储存升高以及关节炎的临床表型促进与尿酸盐关节沉积物相关的炎症反应。少数属性受试者的子集。可变，包括急性关节炎的自由和程度，并发展为可触觉的皮质tophi，慢性关节炎和侵蚀性关节损害未得到定义新目标和生物标志物痛风和侵蚀性关节疾病的进展。应用是在这些来临中缩小知识的主要差距，这项工作将是范式变化可能确定新的目标，以防止和限制痛风相关的病态除了痛风以外的某些关节病，表明改变了胶质胶质糖蛋白诸如粘蛋白型边界luubricant Lubricin之类的成分，并通过一个活性尿酸身份不明的运输机制在痛风的发展中起作用。成纤维细胞细胞（FLS），润滑剂和型粘蛋白型extracellarr的机械连接的变化基质O-糖蛋白，并增加尿酸盐的秘密素，一种促进“常见痛风”的机械性LOP，和慢性破坏性滑膜炎的进展。遗传学方法分析高度不寻常的观察，尤其是痛风的案例作为“ 大自然”。概率是一种原本健康的患有高尿酸血症的女性，在22岁时发作带有经典脚趾关节的小型和国际关节的髋关节炎和不对称的急性痛风关节炎痛风侵蚀和痛风明确确认。血清糖基质，蛋白质组学和糖蛋白质组学表明在肿瘤蛋白和肿瘤的生物合成中失调基因。候选物在TMEM171的“反应组”中很高，这是一种未完全表征的跨膜分子与尿酸酯的转运有关，最近被定义为痛风的敏感性基因。 TMEM171反应组成分超过20个参与糖蛋白生物合成的分子，超过10个粘膜蛋白。滑膜外基质生物学，尿酸盐代谢和运输，Tophus之间的新型交集形成和滑膜炎包括建立新的疾病范式潜在的新生物标志物以及新型O-糖蛋白剂类别的痛风疗法。