Prostaglandin E synthase in rheumatoid arthritis

类风湿性关节炎中的前列腺素 E 合酶

• 批准号: 7345464
• 负责人: Leslie J Crofford
• 金额: $ 30.97万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7345464
• 关键词: Adjuvant Arthritis; Anabolism; Ankylosing spondylitis; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Arthritis; Biological; Bone Marrow; CD4 Positive T Lymphocytes; Cardiovascular system; Cell Fractionation; Cell Line; Cell membrane; Cells; Clinical; Collagen; Collagen Arthritis; Condition; Coxibs; Data; Degenerative polyarthritis; Dendritic Cells; Dinoprostone; Effectiveness; Eicosanoid Production; Eicosanoids; Embryo; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzyme-Linked Immunosorbent Assay; Enzymes; Epithelial; Epoprostenol; Event; Fatty Acids; Fibroblasts; Genotype; Glutathione; Goals; Helper-Inducer T-Lymphocyte; High Pressure Liquid Chromatography; Human; Human Cell Line; Immune; Immune response; Immunization; In Vitro; Incidence; Inflammation; Inflammatory; Inflammatory Response; Interleukin-4; Interleukins; Joints; K/BxN model; Kidney; Knockout Mice; Localized; Measures; Mediating; Modeling; Monoclonal Antibody HuM291; Muromonab-CD3; Mus; Nonesterified Fatty Acids; Numbers; Pain; Pathway interactions; Patients; Peritoneal Macrophages; Pharmaceutical Preparations; Phenotype; Principal Investigator; Production; Prostaglandin Production; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Prostaglandins E; Prostaglandins I; Protein Isoforms; RNA; RNA Interference; Rattus; Relative (related person); Reporting; Research Personnel; Resistance; Rheumatoid Arthritis; Risk; Role; Serum; Shapes; Site; Splenocyte; Staining method; Stains; Swelling; Symptoms; Synovial Cell; Therapeutic Intervention; Time; Tissues; Toxic effect; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; acquired immunity; base; cell type; cyclooxygenase 1; cyclooxygenase 2; cytokine; eicosanoid metabolism; enzyme biosynthesis; gastrointestinal; human TNF protein; in vivo; inhibitor/antagonist; macrophage; mouse PGE synthase 1; neutrophil; progesterone 11-hemisuccinate-(2-iodohistamine); programs; prostaglandin E synthase; response; synthetic enzyme

DESCRIPTION (provided by applicant): The effectiveness of non-steroidal anti-inflammatory drugs and specific cyclooxygenase (COX)-2 inhibitors for treatment of arthritis provides clinical evidence that increased prostaglandin (PG) production in joint tissues contributes to symptoms of pain, swelling, and stiffness. PG biosynthesis requires the sequential action of COX and PG synthase enzymes. After stimulation with pro-inflammatory cytokines, there is a preferential increase in PGE2 in many different cell types, including synovial fibroblasts. We demonstrated that increased PGE2 in response to pro-inflammatory cytokines in human primary synovial cells is due to induction of microsomal PGE synthase (mPGES)-1. The overall goal of this proposal is to characterize the role of mPGES-1 and other PGE synthases in eicosanoid biosynthesis in immune inflammatory arthritis. We hypothesize a requirement for mPGES-1 to achieve maximal PGE2 production and a role for mPGES-1-derived PGE2 in shaping the immune inflammatory response. We propose to determine the specific role of mPGES-1 relative to other synthetic enzymes for biosynthesis of PGE2 in human synovial fibroblasts using specific COX enzyme inhibitors and inhibitory RNA (RNAi). We will investigate eicosanoid production pathways in cells from mice deficient for COX-1, COX-2 or mPGES-1. Expression of the COX and PGES enzymes in synovial tissues from patients with arthritis or non-arthritic subjects and their relative subcellular localization will be determined. In addition, we will examine the consequences of mPGES-1 deficiency for innate and acquired immunity in genetically null mice. We will determine eicosanoid and cytokine profiles of macrophages, splenocytes, and dendritic cells in mPGES-1 null mice. We will determine the impact of mPGES-1 deficiency on dendritic cell phenotype and function. We will determine the role of PGE2 on immune versus inflammatory mechanisms of arthritis using the collagen-induced arthritis and K/BxN serum models. These data will provide the scientific basis by which to determine if mPGES-1 is an appropriate target for therapeutic intervention in arthritis.

描述（由申请人提供）： 非甾体类抗炎药和特异性环氧酶（COX）-2抑制剂治疗关节炎的有效性提供了临床证据，表明关节组织中前列腺素（PG）产生增加，从而有助于疼痛，肿胀和僵硬。 PG生物合成需要COX和PG合酶的顺序作用。用促炎性细胞因子刺激后，在包括滑膜成纤维细胞在内的许多不同细胞类型中，PGE2优先增加。我们证明，人类原代滑膜细胞中促炎细胞因子的PGE2增加是由于诱导微粒体PGE合酶（MPGES）-1所致。该提案的总体目的是表征MPGES-1和其他PGE合酶在免疫炎性关节炎中eicosanaiy Biosynsess中的作用。我们假设对MPGES-1的需求，以实现最大PGE2产生，以及MPGES-1衍生的PGE2在塑造免疫炎症反应中的作用。我们建议使用特定的COX酶抑制剂和抑制性RNA（RNAI）来确定MPGES-1相对于其他合成酶在人类滑膜成纤维细胞中PGE2生物合成的特定作用。我们将研究来自缺乏COX-1，COX-2或MPGES-1的小鼠细胞中的类花生酸生产途径。将确定关节炎或非关节炎患者的滑膜组织中COX和PGES酶的表达及其相对亚细胞定位。此外，我们将研究MPGES-1缺乏症对遗传无效小鼠先天和获得的免疫力的后果。我们将确定巨噬细胞，脾细胞和树突状细胞MPGES-1 NULL小鼠中的eicosanoid和细胞因子谱。我们将确定MPGES-1缺乏对树突状细胞表型和功能的影响。我们将使用胶原蛋白诱导的关节炎和K/BXN血清模型来确定PGE2对关节炎免疫与炎症机制的作用。这些数据将提供科学的基础，以确定MPGES-1是否是治疗关节炎治疗的适当靶标。