PHARMACOLOGY OF ANTIRHEUMATIC AGENTS
抗风湿药的药理学
基本信息
- 批准号:2413978
- 负责人:
- 金额:$ 15.71万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1995
- 资助国家:美国
- 起止时间:1995-07-10 至 1998-04-30
- 项目状态:已结题
- 来源:
- 关键词:adenosine antirheumatic agents biological signal transduction connective tissue pharmacology disease /disorder model drug interactions enzyme activity high performance liquid chromatography human subject inflammation laboratory mouse leukocytes methotrexate pharmacokinetics phosphoprotein phosphatase purinergic receptor rheumatoid arthritis transmethylation
项目摘要
We have recently made the surprising discovery that adenosine mediates the
antiinflammatory effects of methotrexate (MTX), one of the most effective
agents used in the treatment of rheumatoid arthritis. Our observations
suggest that MTX increases adenosine concentrations at inflammed sites by
inhibiting 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR)
transformylase thereby increasing intracellular concentrations of AICAR.
Intracellular accumulation of AICAR increases extracellular adenosine
concentration by an unknown mechanism. To determine how MTX diminishes
inflammation we propose to: 1. Examine the biochemical mechanism by which
MTX increases extracellular adenosine concentrations of MTX (and its
polyglutamates) that accumulate in human fibroblasts and endothelial
cells, the concentrations of AICAR, inosine and adenine nucleotides in
MTX-treated cells and the direct effect of MTX treatment on the activity
of the enzymes most directly involved in regulation of adenosine release:
adenosine deaminase, adenosine kinase and AMP deaminase. We will
determine the concentration of nucleotides in the amount of adenosine
release from and activity of adenosine-regulating enzymes in peripheral
blood mononuclear cells of patients with RA before and 6 weeks after onset
of treatment with MTX. 2. Examine signal transduction pathway at
leukocyte adenosine A/2/A receptors. Although cAMP has been thought to
mediate the effects of adenosine receptor ligation we have found evidence
to indicate that adenosine inhibits leukocyte function via the cAMP-
independent activation of a protein phosphatase (most likely protein
phosphatase 1, pp1). To better understand signal transduction at
adenosine receptors we will study adenosine receptor-stimulated protein
phosphatase activity directly, adenosine-mediated translocation of protein
phosphatases within the cell, effects of adenosine receptor occupancy on
association of pp1 with regulatory proteins and molecular identification
of pp1 regulatory proteins and substrates in the neutrophil. 3. Test the
complementary hypothesis that the antiinflammatory effects of MTX result,
in part, from inhibition of transmethylation reactions required for post-
translational modification of proteins and lipids by examining
transmethylation reactions directly. 4. Study the mechanism by which MTX
inhibits chronic inflammation in animal models (collagen arthritis) and
patients with rheumatoid arthritis. We will study the effect of
monoclonal antiadenosine receptor antibodies on MTX inhibition of
inflammation in appropriate animal models. To show evidence for
adenosine-mediated suppression of inflammation in patients treated with
MTX we will compare adenosine receptor expression on leukocytes from
peripheral blood to those obtained from synovial fluid to establish
whether there has been ligand-mediated down-regulation of adenosine
receptors. We have designed these studies to improve our understanding of
the antiinflammatory properties of MTX and we believe that the information
gained from these studies will permit the development of more specific and
less toxic therapeutic regimens for use in the therapy of rheumatoid
arthritis and other chronic inflammatory diseases.
我们最近有了惊人的发现腺苷介导
项目成果
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BRUCE Neil CRONSTEIN其他文献
BRUCE Neil CRONSTEIN的其他文献
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{{ truncateString('BRUCE Neil CRONSTEIN', 18)}}的其他基金
Engineering Personalized Devices for Craniomaxillofacial Defects
针对颅颌面缺陷设计个性化设备
- 批准号:
10116988 - 财政年份:2019
- 资助金额:
$ 15.71万 - 项目类别: