The A2a adenosine receptor modulates hyaluronan mediated lung inflammation

A2a 腺苷受体调节透明质酸介导的肺部炎症

基本信息

  • 批准号:
    7319124
  • 负责人:
  • 金额:
    $ 36.9万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2007
  • 资助国家:
    美国
  • 起止时间:
    2007-07-15 至 2011-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): It is becoming increasingly clear that the tissue microenvironment plays a critical role in regulating inflammation and tissue destruction. Chronic inflammation and tissue fibrosis lead not only to an influx of inflammatory cells/mediators and turnover of the extracellular matrix, but also to increased extracellular concentrations of the purine nucleotide adenosine. Recently fragments of the extracellular matrix component hyaluronan (HA) have been shown to play a central role in the development of lung inflammation and fibrosis in animal models. Similarly, adenosine has been shown to be a crucial negative regulator of inflammation and tissue protector from immune destruction. We posit that the extracellular matrix is both the target of inflammation and a central activator of inflammatory cells and that adenosine is a key modulator of HA-induced inflammation. We hypothesize that within the tissue microenvironment, a critical mechanism by which adenosine exerts its anti-inflammatory effects is by modulating HA fragment induced tissue injury via engagement of the A2a adenosine receptor (A2aR). Interestingly, LMW HA fragments may also augment inflammation by down regulating expression and function of this anti-inflammatory A2aR. Thus the ultimate outcome of tissue inflammation is in part dictated by the interplay between LMW HA fragments and tissue derived adenosine. To this end, in Specific Aim 1, we hypothesize that A2aR ligation modulates HA fragment-induced inflammatory gene expression. We will perform studies in macrophages and airway and alveolar epithelial cells to define the molecular pathway by which adenosine, via A2aR engagement, modulates HA-induced gene expression. In Specific Aim 2, we hypothesize that LMW HA augments inflammation by downregulating the anti-inflammatory A2aR. We will perform studies to define the molecular mechanisms by which LMW HA modulates A2aR expression. Specific Aim 3 hypothesizes that endogenous adenosine modulates bleomycin-induced lung inflammation and fibrosis and that pharmacologic administration of A2aR agonists can protect against disease. We will perform in vivo experiments to demonstrate that bleomycin injury is worse in the absence of A2aR expression. Furthermore, we will define the role of A2aR stimulation on macrophages, and lung airway and alveolar epithelial cells in mediating this protective effect. By defining the pro- and anti-inflammatory properties of extra cellular matrix components, we will be better able to identify specific pharmacologic targets as potential therapies. We believe that these studies will provide the pre-clinical basis for the use of A2aR specific agonists in the treatment of inflammatory lung diseases such as idiopathic pulmonary fibrosis, chronic bronchitis and emphysema.
描述(由申请人提供):越来越清楚的是,组织微环境在调节炎症和组织破坏中起着关键作用。慢性炎症和组织纤维化不仅导致炎性细胞/介质的流入和细胞外基质的周转,而且导致嘌呤核苷酸腺苷的细胞外浓度增加。最近,细胞外基质组分透明质酸(HA)的片段已被证明在动物模型中的肺部炎症和纤维化的发展中发挥核心作用。类似地,腺苷已被证明是炎症的重要负调节剂和免疫破坏的组织保护剂。我们认为细胞外基质既是炎症的靶点,又是炎症细胞的中枢激活剂,腺苷是HA诱导的炎症的关键调节剂。我们假设,在组织微环境中,腺苷发挥其抗炎作用的关键机制是通过与A2 a腺苷受体(A2 aR)结合来调节HA片段诱导的组织损伤。有趣的是,LMW HA片段也可以通过下调这种抗炎A2 aR的表达和功能来增加炎症。因此,组织炎症的最终结果部分取决于LMW HA片段和组织来源的腺苷之间的相互作用。为此,在特异性目的1中,我们假设A2 aR连接调节HA片段诱导的炎症基因表达。我们将在巨噬细胞、气道和肺泡上皮细胞中进行研究,以确定腺苷通过A2 aR参与调节HA诱导的基因表达的分子途径。在特定目标2中,我们假设LMW HA通过下调抗炎A2 aR来增强炎症。我们将进行研究,以确定LMW HA调节A2 aR表达的分子机制。具体目标3假设内源性腺苷调节博来霉素诱导的肺部炎症和纤维化,并且A2 aR激动剂的药理学给药可以预防疾病。我们将进行体内实验,以证明博莱霉素损伤是在A2 aR表达的情况下更糟。此外,我们将确定A2 aR刺激巨噬细胞,肺气道和肺泡上皮细胞介导这种保护作用的作用。通过确定细胞外基质成分的促炎和抗炎特性,我们将能够更好地确定作为潜在疗法的特定药理学靶点。我们相信这些研究将为A2 aR特异性激动剂在治疗炎性肺病如特发性肺纤维化、慢性支气管炎和肺气肿中的应用提供临床前基础。

项目成果

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Maureen Renee Horton其他文献

Maureen Renee Horton的其他文献

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{{ truncateString('Maureen Renee Horton', 18)}}的其他基金

Immunotherapy induced Trm arrest and reverse lung fibrosis
免疫疗法诱导 Trm 阻滞并逆转肺纤维化
  • 批准号:
    9898457
  • 财政年份:
    2018
  • 资助金额:
    $ 36.9万
  • 项目类别:
mTORC1 and mTORC2 selectively regulate macrophage differentiation
mTORC1 和 mTORC2 选择性调节巨噬细胞分化
  • 批准号:
    8389618
  • 财政年份:
    2012
  • 资助金额:
    $ 36.9万
  • 项目类别:
mTORC1 and mTORC2 selectively regulate macrophage differentiation
mTORC1 和 mTORC2 选择性调节巨噬细胞分化
  • 批准号:
    8223936
  • 财政年份:
    2012
  • 资助金额:
    $ 36.9万
  • 项目类别:
The A2a adenosine receptor modulates hyaluronan mediated lung inflammation
A2a 腺苷受体调节透明质酸介导的肺部炎症
  • 批准号:
    7876810
  • 财政年份:
    2007
  • 资助金额:
    $ 36.9万
  • 项目类别:
The A2a adenosine receptor modulates hyaluronan mediated lung inflammation
A2a 腺苷受体调节透明质酸介导的肺部炎症
  • 批准号:
    7642269
  • 财政年份:
    2007
  • 资助金额:
    $ 36.9万
  • 项目类别:
The A2a adenosine receptor modulates hyaluronan mediated lung inflammation
A2a 腺苷受体调节透明质酸介导的肺部炎症
  • 批准号:
    7471389
  • 财政年份:
    2007
  • 资助金额:
    $ 36.9万
  • 项目类别:
Hyaluronan-induced signaling and gene regulation
透明质酸诱导的信号传导和基因调控
  • 批准号:
    6794682
  • 财政年份:
    2003
  • 资助金额:
    $ 36.9万
  • 项目类别:
Hyaluronan-induced signaling and gene regulation
透明质酸诱导的信号传导和基因调控
  • 批准号:
    6920810
  • 财政年份:
    2003
  • 资助金额:
    $ 36.9万
  • 项目类别:
Hyaluronan-Induced Signaling and Gene Regulation
透明质酸诱导的信号传导和基因调控
  • 批准号:
    7578717
  • 财政年份:
    2003
  • 资助金额:
    $ 36.9万
  • 项目类别:
Hyaluronan-induced signaling and gene regulation
透明质酸诱导的信号传导和基因调控
  • 批准号:
    7092579
  • 财政年份:
    2003
  • 资助金额:
    $ 36.9万
  • 项目类别:

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