Regulation of the A2a receptor by extracellular matrix fragments

细胞外基质片段对 A2a 受体的调节

基本信息

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
项目类别：
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

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

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项目摘要

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至关重要的作用。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中起着至关重要的作用。随着ECM在炎症期间降解，低分子量透明质酸（LMW HA）片段通常在愈合过程中被清除。但是，在持续的炎症中，组织微环境中LMW HA碎片的持续性破坏和持续存在。除LMW HA外，炎症后的组织微环境中还存在腺苷。腺苷充当炎症和组织破坏的负调节剂，特别是彻底的腺苷A2A受体（A2AR）参与。我们提出以LMW HA片段的形式提出降解的透明质酸，它通过下调A2AR的表达，从而防止其抗炎作用来调节免疫反应的大小和质量。因此，炎症的结果取决于促炎性LMW HA与抗炎A2A受体之间的相互作用。了解ECM增加炎症能力的途径可能会导致药物干预的潜在靶标。我们认为，我们的研究将确定一种新的机制，通过该机制，LMW HA向下调节抗炎A2AR，从而促进炎症导致组织纤维化。