Regulation of the A2a receptor by extracellular matrix fragments

细胞外基质片段对 A2a 受体的调节

• 批准号: 7808553
• 负责人: Samuel Lester Collins
• 金额: $ 5.05万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-16 至 2011-09-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7808553
• 关键词: Adenosine; Anti-Inflammatory Agents; Anti-inflammatory; Bleomycin; CD44 gene; Cells; Cessation of life; Data; Down-Regulation; ECM receptor; Endothelial Cells; Enzymes; Epithelial; Extracellular Matrix; Extracellular Space; Fibrosis; Gene Expression; Genes; Healed; Homeostasis; Hyaluronan; Immune; Immune response; Immune system; Inflammation; Inflammatory; Injury; Intervention; Knockout Mice; Lead; Lung; Mediating; Modeling; Molecular Weight; Outcome; Pathway interactions; Play; Process; Production; Purine Nucleotides; Recruitment Activity; Regulation; Resistance; Role; Severity of illness; Signal Transduction; T-Lymphocyte; Tissues; Transgenic Mice; Up-Regulation; Water; cytokine; extracellular; healing; in vivo; indium-bleomycin; interest; lung injury; macrophage; mortality; novel; prevent; receptor; receptor expression; receptor function

DESCRIPTION (provided by applicant): The tissue microenvironment plays a critical role in regulating inflammation. Extracellular matrix (ECM) breakdown products are not only a byproduct of inflammation but play an essential role in controlling the duration and intensity of the inflammation. As the ECM is degraded during inflammation, low molecular weight hyaluronan (LMW HA) fragments are generated that are normally cleared during the healing process. However, during continual inflammation there is ongoing tissue destruction and persistence of LMW HA fragments in the tissue microenvironment. In addition to LMW HA, adenosine is present in the tissue microenvironment following inflammation. Adenosine acts as a negative regulator of inflammation and tissue destruction specifically thorough adenosine A2a receptor (A2aR) engagement. We propose degraded hyaluronan, in the form of LMW HA fragments, plays an important role in modulating the magnitude and quality of an immune response by down-regulating the expression of the A2aR thereby preventing its anti-inflammatory effects. Thus, the outcome of inflammation is determined by the interplay between pro-inflammatory LMW HA and the anti-inflammatory A2a receptor. An understanding of the pathways underlying the ability of ECM to augment inflammation may lead to potential targets for pharmacologic intervention. We believe that our studies will identify a novel mechanism by which LMW HA down regulates the anti-inflammatory A2aR thus promoting inflammation leading to tissue fibrosis.

描述（由申请人提供）：组织微环境在调节炎症中起着关键作用。细胞外基质（ECM）分解产物不仅是炎症的副产品，而且在控制炎症的持续时间和强度方面发挥着重要作用。由于 ECM 在炎症过程中降解，会产生低分子量透明质酸 (LMW HA) 碎片，这些碎片通常会在愈合过程中被清除。然而，在持续的炎症过程中，组织不断遭到破坏，并且 LMW HA 片段在组织微环境中持续存在。除了 LMW HA 之外，炎症后的组织微环境中还存在腺苷。腺苷作为炎症和组织破坏的负调节剂，特别是通过腺苷 A2a 受体 (A2aR) 参与。我们认为，LMW HA 片段形式的降解透明质酸通过下调 A2aR 的表达从而防止其抗炎作用，在调节免疫反应的强度和质量方面发挥着重要作用。因此，炎症的结果是由促炎LMW HA和抗炎A2a受体之间的相互作用决定的。了解 ECM 增强炎症能力的潜在途径可能会导致药物干预的潜在目标。我们相信，我们的研究将确定 LMW HA 下调抗炎 A2aR 从而促进炎症导致组织纤维化的新机制。