Accelerated arthritis in E and P selectin deficient mice

E 和 P 选择素缺陷小鼠的关节炎加速

• 批准号: 7185814
• 负责人: JEFFREY HAROLD RUTH
• 金额: $ 5.66万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-15 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7185814
• 关键词: Animal Model; Antibodies; Antigens; Arthritis; Attenuated; Autoimmune Diseases; Blood Platelets; Bone Resorption; Cell Adhesion; Cell Adhesion Molecules; Cell Wall; Cells; Chronic; Collagen; Complex; Cytokine Network Pathway; Data; Defect; Dermal; Development; Disease; Dyes; E-Selectin; Endothelial Cells; Endothelium; Engineering; Environment; Enzyme-Linked Immunosorbent Assay; Equilibrium; Excision; Fluorescent Dyes; Generations; Genes; Immune system; Immunohistochemistry; Incidence; Inflammation; Inflammatory; Inflammatory Response; Intercellular adhesion molecule 1; Interleukin-13; Interleukin-15; Interleukin-18; Interleukin-4; Interleukins; Joints; Kinetics; Leucocytic infiltrate; Leukocytes; Link; Maintenance; Modeling; Monoclonal Antibodies; Monokines; Mus; Neutrophil Infiltration; Numbers; P-Selectin; Pathology; Peritoneal; Personal Satisfaction; Polymerase Chain Reaction; Population; Process; Production; Property; Rattus; Recruitment Activity; Regulation; Reverse Transcriptase Polymerase Chain Reaction; Role; SELE gene; SELP gene; Score; Selectins; Serum; Serum Proteins; Severities; Site; Synovial Fluid; Synovial Membrane; System; T-Lymphocyte; TNF gene; Tail; Therapeutic; Time; Tissues; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Veins; Wild Type Mouse; Work; cell motility; chemokine; cytokine; day; design; human TNF protein; in vivo; insight; lymph nodes; macrophage; man; migration; novel; null mutation

DESCRIPTION (provided by applicant): Adhesion molecule expression dictates the type of inflammatory response initiated, therefore the development of therapeutics designed at inhibiting adhesion molecule function seem very worthwhile. However, our preliminary data indicates that selective adhesion molecule inhibition may amplify certain inflammatory responses. Thus, compensatory adhesion molecule expression may be functioning in this in vivo environment and may work in a similar fashion as cytokine networks. For example, it is well established that IL-13 has many properties similar to IL-4. Likewise, IL-15 has redundant properties to IL-2, and IL-1beta has similar properties to IL-18. It may be that as the immune system became more sophisticated, there evolved built in backup mechanisms, attenuating the overall importance of any 1 cytokine. Therefore, as observed with cytokine networks, certain adhesion molecules may compensate for missing or antagonized ones. Overall, this proposal will provide novel insight pertaining to the initiation and maintenance of inflammation by linking adhesion molecule expression, monokine regulation, and leukocyte recruitment. These studies will demonstrate the complexity involved in targeting adhesion molecules as a potential therapeutic strategy for the treatment of RA and other inflammatory disorders. While common dogma suggests IL-1beta regulates selectins, this study proposes the novel hypothesis that in vivo E- and P-selectins regulate IL-1beta production and CIA development.

描述（由申请人提供）：粘附分子表达决定了引发的炎症反应的类型，因此开发旨在抑制粘附分子功能的治疗方法似乎非常值得。然而，我们的初步数据表明，选择性粘附分子抑制可能会放大某些炎症反应。因此，补偿性粘附分子表达可能在这种体内环境中起作用，并且可能以与细胞因子网络类似的方式起作用。例如，众所周知，IL-13 具有许多与 IL-4 类似的特性。同样，IL-15 具有与 IL-2 多余的特性，IL-1beta 与 IL-18 具有相似的特性。随着免疫系统变得更加复杂，可能会进化出内置的备份机制，从而削弱任何一种细胞因子的整体重要性。因此，正如在细胞因子网络中观察到的那样，某些粘附分子可能会补偿缺失或拮抗的粘附分子。总体而言，该提案将通过将粘附分子表达、单核因子调节和白细胞募集联系起来，为炎症的引发和维持提供新的见解。这些研究将证明靶向粘附分子作为治疗 RA 和其他炎症性疾病的潜在治疗策略所涉及的复杂性。虽然普遍认为 IL-1beta 调节选择素，但本研究提出了新的假设，即体内 E-和 P-选择素调节 IL-1beta 的产生和 CIA 的发育。