Targeting DAMPs in Alcoholic Hepatitis

针对酒精性肝炎中的 DAMP

基本信息

项目摘要

DESCRIPTION (provided by applicant): Alcoholic hepatitis (AH) is particularly severe form of alcoholic liver disease (ALD) that affects up to 20% of alcoholics and has a high mortality rate. However, the molecular pathways that trigger AH remain unknown, and therapy for alcoholic hepatitis has not changed over the past 30 years. Notably, targeting inflammatory cytokines such as TNFα or decreasing ROS production have been unsuccessful, and non-specific anti- inflammatory therapy with corticosteroids is only moderately effectively. In this proposal, we will investigate the hypothesis that signature molecules from dying cells, termed damage-associated molecular patterns (DAMPs), contribute to hepatic and systemic inflammation in AH, progenitor cell proliferation, and worsen liver injury and outcome. The proposed research will investigate several DAMPs with known role in sterile inflammation and neutrophil recruitment in the liver with a particular focus on (i) mitochondrial (mt) DAMPs due to their abundance in hepatoyctes and mitochondrial changes in ALD, and (ii) HMGB1, a key DAMP in necrotic liver injury. Our application will employ a combination of human studies in patients with AH and functional mouse studies, to identify key and druggable DAMP pathways with high relevance to AH. The proposed human studies will be performed in collaboration with Project 1, the Human Biorepository Core and the 10 clinical centers of the InTeam Consortium. For functional studies, we will test DAMP pathways in acute-on-chronic models of AH developed together with and performed in part by the Mouse Models Core of this consortium. We will determine the contribution of HMGB1 to AH by measuring HMGB1 levels in AH patients, and determining the contribution of HMGB1 and its receptor RAGE in two acute-on-chronic models of AH in novel conditional HMGB1 knockout mice and RAGE-deficient mice, respectively (Aim 1). To determine the contribution of mtDAMPs formyl peptide, mtDNA and ATP to AH, we will measure mtDNA, formyl peptide receptor 1 (FPR1), P2X7 receptor and Toll-like receptor 9 in patients, and determine their functional contribution in murine AH models using P2X7, FPR1 and TLR9 knockout mice (Aim 2). For both Aim 1 and Aim 2, DAMP and DAMP receptor levels measured in AH patients will be also correlated with clinical parameters and next generation RNA sequencing data generated in Project 1 of this consortium. Finally, we will determine the effect of pharmacologic DAMP and DAMP receptor inhibition for the prevention and treatment of murine AH focusing on inhibition of those pathways that showed the most significant contribution in Aims 1 and 2 (Aim 3). We anticipate to unravel the contribution of DAMPs to hepatic and systemic inflammation in AH, and to establish select DAMPs and their receptors as "druggable" targets in AH.
描述(由适用提供):酒精性肝炎(AH)是酗酒肝病(ALD)特别严重的形式,影响多达20%的酒精中毒,并且死亡率很高。但是,在过去30年中,触发AH的分子途径仍然未知,酒精性肝炎的治疗没有改变。值得注意的是,靶向诸如TNFα或ROS产生降低的炎症细胞因子已经不成功,并且对皮质类固醇的非特异性抗炎疗法仅是有效的。在该提案中,我们将研究以下假设:垂死细胞中的特征分子,称为损伤相关的分子模式(DAMP),有助于AH中的肝和全身感染,祖细胞增殖以及较差的生活损伤和结果。拟议的研究将调查几种在肝脏中无菌感染和中性粒细胞募集中具有已知作用的潮湿,特别侧重于(i)线粒体(MT)潮湿,因为它们在ALD中的肝酸性丰富和线粒体变化中的丰富性,以及(II)HMGB1,HMGB1,Necratiotor necratioto necrato necrato necriver in ecriver in ecriver in ecriver in ecriver in ecriver in ecriver inecrain inecrain inecraget necrain necrain livir in ecriver necriver inecrains necrain liver inecrain。我们的应用将在AH患者和功能小鼠研究的患者中采用人类研究的结合,以识别与AH相关的关键和可药物潮湿途径。拟议的人类研究将与项目1,人类生物座核和Inteam联盟的10个临床中心合作进行。对于功能研究,我们将测试与该财团的小鼠模型核心一起开发并部分进行的AH急性chronic模型中的潮湿途径。我们将通过测量AH患者的HMGB1水平来确定HMGB1对AH的贡献,并确定HMGB1及其接收器在新的有条件的HMGB1敲除小鼠和rage缺乏小鼠中AH的两个急性chron-chronic模型中的贡献(AIM 1)。为了确定MTDAMPS甲基肽,mtDNA和ATP对AH的贡献,我们将在患者中测量MTDNA,甲基肽受体1(FPR1),P2X7受体和类似Toll样受体9,并使用P2X7,FPR1和TLR9敲除鼠标(AINCOUT MENCITE)(AINCOUT MENCTIC)在鼠类AH模型中确定其功能贡献。 AIM 1和AIM 2,在AH患者中测量的潮湿受体和潮湿受体水平都将与该财团项目1中产生的临床参数和下一代RNA测序数据相关。最后,我们将确定药物潮湿和潮湿受体抑制对预防和治疗鼠AH的影响,重点是抑制那些在目标1和2中显示出最重要贡献的途径(AIM 3)。预计会在AH中揭示潮湿对肝炎和全身注射的贡献,并将某些湿气及其接收器建立为AH中的“可药物”靶标。

项目成果

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WAJAHAT Zafar MEHAL其他文献

WAJAHAT Zafar MEHAL的其他文献

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{{ truncateString('WAJAHAT Zafar MEHAL', 18)}}的其他基金

Inhibition of Sterile Inflammation by Digoxin in Alcoholic Hepatitis
地高辛抑制酒精性肝炎无菌性炎症
  • 批准号:
    10428621
  • 财政年份:
    2018
  • 资助金额:
    $ 37.76万
  • 项目类别:
Inhibition of Sterile Inflammation by Digoxin in Alcoholic Hepatitis
地高辛抑制酒精性肝炎无菌性炎症
  • 批准号:
    9791135
  • 财政年份:
    2018
  • 资助金额:
    $ 37.76万
  • 项目类别:
Inhibition of Sterile Inflammation by Digoxin in Alcoholic Hepatitis
地高辛抑制酒精性肝炎无菌性炎症
  • 批准号:
    10190740
  • 财政年份:
    2018
  • 资助金额:
    $ 37.76万
  • 项目类别:
Regulation of Liver Fibrosis by Pyruvate Kinase M2 (PKM2)
丙酮酸激酶 M2 (PKM2) 对肝纤维化的调节
  • 批准号:
    10513289
  • 财政年份:
    2016
  • 资助金额:
    $ 37.76万
  • 项目类别:
Cell-free DNA is a driver of non-alcoholic steatohepatitis via TLR9 activation
游离 DNA 通过 TLR9 激活驱动非酒精性脂肪性肝炎
  • 批准号:
    9378394
  • 财政年份:
    2016
  • 资助金额:
    $ 37.76万
  • 项目类别:
Targeting DAMPs in Alcoholic Hepatitis
针对酒精性肝炎中的 DAMP
  • 批准号:
    8669780
  • 财政年份:
    2013
  • 资助金额:
    $ 37.76万
  • 项目类别:
Targeting DAMPs in Alcoholic Hepatitis
针对酒精性肝炎中的 DAMP
  • 批准号:
    8427971
  • 财政年份:
    2013
  • 资助金额:
    $ 37.76万
  • 项目类别:
Targeting DAMPs in Alcoholic Hepatitis
针对酒精性肝炎中的 DAMP
  • 批准号:
    9282368
  • 财政年份:
    2013
  • 资助金额:
    $ 37.76万
  • 项目类别:
Sterile Hepatic Inflammation
无菌性肝脏炎症
  • 批准号:
    7929861
  • 财政年份:
    2010
  • 资助金额:
    $ 37.76万
  • 项目类别:
Sterile Hepatic Inflammation
无菌性肝脏炎症
  • 批准号:
    8195933
  • 财政年份:
    2010
  • 资助金额:
    $ 37.76万
  • 项目类别:

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靶向细胞信号通路以破坏药物滥用
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肺缺血再灌注损伤中的 Pannexin-1 信号转导
  • 批准号:
    9898429
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组蛋白读取器 DPF3 对棕色和米色脂肪生成的调节
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