PHARMACOLOGY OF ANTIRHEUMATIC AGENTS

抗风湿药的药理学

基本信息

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

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

BRUCE Neil CRONSTEIN其他文献

BRUCE Neil CRONSTEIN的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('BRUCE Neil CRONSTEIN', 18)}}的其他基金

Clinical and Translational Science Award
临床和转化科学奖
  • 批准号:
    10255087
  • 财政年份:
    2020
  • 资助金额:
    $ 15.71万
  • 项目类别:
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:
Clinical and Translational Science Award
临床和转化科学奖
  • 批准号:
    10183901
  • 财政年份:
    2015
  • 资助金额:
    $ 15.71万
  • 项目类别:
Clinical and Translational Science Award
临床和转化科学奖
  • 批准号:
    10320492
  • 财政年份:
    2015
  • 资助金额:
    $ 15.71万
  • 项目类别:
Clinical and Translational Science Award
临床和转化科学奖
  • 批准号:
    10317650
  • 财政年份:
    2015
  • 资助金额:
    $ 15.71万
  • 项目类别:
Clinical and Translational Science Award
临床和转化科学奖
  • 批准号:
    9085750
  • 财政年份:
    2015
  • 资助金额:
    $ 15.71万
  • 项目类别:
Clinical and Translational Science Award
临床和转化科学奖
  • 批准号:
    10289909
  • 财政年份:
    2015
  • 资助金额:
    $ 15.71万
  • 项目类别:
Clinical and Translational Science Award
临床和转化科学奖
  • 批准号:
    10310799
  • 财政年份:
    2015
  • 资助金额:
    $ 15.71万
  • 项目类别:
Clinical and Translational Science Award
临床和转化科学奖
  • 批准号:
    9252686
  • 财政年份:
    2015
  • 资助金额:
    $ 15.71万
  • 项目类别:
Clinical and Translational Science Award
临床和转化科学奖
  • 批准号:
    10382896
  • 财政年份:
    2015
  • 资助金额:
    $ 15.71万
  • 项目类别:

相似海外基金

PHARMACOLOGY OF ANTIRHEUMATIC AGENTS
抗风湿药的药理学
  • 批准号:
    6305948
  • 财政年份:
    1999
  • 资助金额:
    $ 15.71万
  • 项目类别:
PHARMACOLOGY OF ANTIRHEUMATIC AGENTS
抗风湿药的药理学
  • 批准号:
    6115762
  • 财政年份:
    1998
  • 资助金额:
    $ 15.71万
  • 项目类别:
PHARMACOLOGY OF ANTIRHEUMATIC AGENTS
抗风湿药的药理学
  • 批准号:
    6246913
  • 财政年份:
    1997
  • 资助金额:
    $ 15.71万
  • 项目类别:
PHARMACOLOGY OF ANTIRHEUMATIC AGENTS
抗风湿药的药理学
  • 批准号:
    6276996
  • 财政年份:
    1997
  • 资助金额:
    $ 15.71万
  • 项目类别:
PHARMACOLOGY OF ANTIRHEUMATIC AGENTS
抗风湿药的药理学
  • 批准号:
    2610000
  • 财政年份:
    1995
  • 资助金额:
    $ 15.71万
  • 项目类别:
PHARMACOLOGY OF ANTIRHEUMATIC AGENTS
抗风湿药的药理学
  • 批准号:
    2081090
  • 财政年份:
    1995
  • 资助金额:
    $ 15.71万
  • 项目类别:
PHARMACOLOGY OF ANTIRHEUMATIC AGENTS
抗风湿药的药理学
  • 批准号:
    6374959
  • 财政年份:
    1995
  • 资助金额:
    $ 15.71万
  • 项目类别:
PHARMACOLOGY OF ANTIRHEUMATIC AGENTS
抗风湿药的药理学
  • 批准号:
    6511722
  • 财政年份:
    1995
  • 资助金额:
    $ 15.71万
  • 项目类别:
PHARMACOLOGY OF ANTIRHEUMATIC AGENTS
抗风湿药的药理学
  • 批准号:
    2909797
  • 财政年份:
    1995
  • 资助金额:
    $ 15.71万
  • 项目类别:
PHARMACOLOGY OF ANTIRHEUMATIC AGENTS
抗风湿药的药理学
  • 批准号:
    6171291
  • 财政年份:
    1995
  • 资助金额:
    $ 15.71万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了