Interactions between neutrophils and cholangiocytes in alcoholic hepatitis

酒精性肝炎中中性粒细胞和胆管细胞之间的相互作用

基本信息

  • 批准号:
    10617893
  • 负责人:
  • 金额:
    $ 16.75万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-09-25 至 2026-06-30
  • 项目状态:
    未结题

项目摘要

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, began in late fall of 2019 and now has spread throughout most of the world. As of this writing, there are over 500 million cases worldwide, including over 80 million cases in the US, approximately 987,000 of whom have died from the infection. We analyzed the first 1,827 patients hospitalized with COVID-19 at our institution and found that the liver is usually involved – AST is elevated in over 80% of our patients, while ALT is elevated in over 60% - and infected patients with elevated transaminases are nearly twice as likely to die. Our subsequent clinical-pathological study furthermore showed that most patients who died exhibited hepatic steatosis and inflammation. In addition, it is now appreciated that pre-existing alcohol-associated liver disease (AALD), which typically includes steatohepatitis, is an independent risk factor that increases mortality more than two-fold. Although most patients who die of COVID-19 do not have liver failure, these findings instead raise the possibility that the steatohepatitis that occurs in AALD results in the pro-inflammatory, thrombogenic state responsible for the cardiopulmonary complications that usually cause a more severe and often fatal course. The goal of this project is to determine whether and how alcoholic steatohepatitis synergizes with SARS-CoV-2 infection to exacerbate the pro-inflammatory state associated with a worse outcome, with the ultimate aim of determining therapeutic targets to block this synergy. The specific hypothesis to be tested is that SARS-CoV-2 infection in the setting of AALD causes pathological white blood cell (WBC)-hepatocyte interactions that result in release of inflammatory cytokines markedly exceeding what is caused by SARS-CoV-2 infection or AALD alone. In order to test this, we will ascertain whether white blood cells (WBCs) are responsible for COVID-19 liver damage, and if so, determine which type of WBC is responsible. We also will determine whether the SARS-CoV-2 virus causes direct cytopathic damage to hepatocytes, and whether the hepatocytes are more susceptible to damage if they have steatosis or have been exposed to alcohol. This hypothesis will be tested through three specific aims: (1) We will determine whether and which type of WBCs from COVID-19-infected patients interact with human hepatocytes; (2) We will determine whether steatosis or other intracellular factors make hepatocytes susceptible to damage from the SARS-CoV-2 virus and/or potentiate cytokine release; and (3) Based on these results, we will identify the signaling pathways activated in hepatocytes by WBCs and by direct viral entry that result in hepatocellular damage and cytokine release in COVID-19 infection. This project may have a broad impact on our understanding of how alcohol consumption affects COVID-19 outcomes by determining the mechanism for increased mortality in COVID-19 patients with AALD. The PI is an experienced liver cell biologist and a practicing hepatologist, his primary collaborator is a hepatitis virologist with specific SARS-CoV-2 expertise, and they will take advantage of Yale's NIH-sponsored Liver Center, so the environment is uniquely suited to support this project as well.
由SARS-CoV-2病毒引起的新冠肺炎大流行始于2019年深秋,目前已蔓延 遍及世界大部分地区。在撰写本文时,全世界有超过5亿个病例,其中包括80多个 美国有100万病例,其中约98.7万人死于感染。我们分析了第一个 1,827例因新冠肺炎入院治疗的患者发现肝脏通常受累--天冬氨酸转氨酶 超过80%的患者升高,而超过60%的ALT升高-感染患者升高 转氨酶死亡的可能性几乎是前者的两倍。我们随后的临床病理研究进一步显示 大多数死亡的患者都表现出肝脏脂肪变性和炎症。此外,现在人们认识到, 既往存在的酒精相关性肝病(AALD),通常包括脂肪性肝炎,是一种独立的 使死亡率增加两倍以上的风险因素。尽管大多数死于新冠肺炎的患者没有 肝功能衰竭,这些发现反而增加了发生在AALD中的脂肪性肝炎导致 促炎、血栓形成状态导致心肺并发症,通常会导致 更严重的,通常是致命的病程。这个项目的目标是确定酒精是否和如何酗酒 脂肪性肝炎与SARS-CoV-2感染协同作用加剧与以下疾病相关的促炎状态 更糟糕的结果,最终目的是确定治疗靶点以阻止这种协同作用。具体的 有待检验的假设是,在急性酒精性肝病的情况下,SARS-CoV-2感染会导致病理性白细胞 (WBC)-肝细胞相互作用导致炎症细胞因子的释放明显超过 由SARS-CoV-2感染或AALD单独引起。为了测试这一点,我们将确定白细胞 白血球(WBC)是新冠肺炎肝脏损害的罪魁祸首,如果是这样,请确定哪种类型的白血球应对此负责。我们 也将确定SARS-CoV-2病毒是否对肝细胞造成直接的细胞病变损害,以及 如果肝细胞有脂肪变性或暴露在酒精中,它们更容易受到损害。这 假设将通过三个具体目标进行检验:(1)我们将确定是否存在以及哪种类型的WBC 新冠肺炎感染患者的脂肪与人类肝细胞相互作用;(2)我们将确定脂肪变性或 其他细胞内因素使肝细胞容易受到SARS-CoV-2病毒的损害和/或增强 细胞因子的释放;(3)基于这些结果,我们将确定肝细胞中激活的信号通路 通过白细胞和直接病毒进入导致新冠肺炎肝细胞损伤和细胞因子释放 感染。这个项目可能会对我们理解酒精消费如何影响我们产生广泛的影响 通过确定新冠肺炎急性酒精性肝病患者死亡率增加的机制来评估新冠肺炎的预后。 PI是一位经验丰富的肝细胞生物学家和执业肝病专家,他的主要合作者是一种肝炎 拥有SARS-CoV-2专业知识的病毒学家,他们将利用耶鲁大学NIH赞助的肝脏 中心,所以这个环境也非常适合支持这个项目。

项目成果

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MICHAEL H NATHANSON其他文献

MICHAEL H NATHANSON的其他文献

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{{ truncateString('MICHAEL H NATHANSON', 18)}}的其他基金

Yale Liver Center
耶鲁肝脏中心
  • 批准号:
    10388648
  • 财政年份:
    2021
  • 资助金额:
    $ 16.75万
  • 项目类别:
Interactions between neutrophils and cholangiocytes in alcoholic hepatitis
酒精性肝炎中中性粒细胞和胆管细胞之间的相互作用
  • 批准号:
    10298412
  • 财政年份:
    2021
  • 资助金额:
    $ 16.75万
  • 项目类别:
Interactions between neutrophils and cholangiocytes in alcoholic hepatitis
酒精性肝炎中中性粒细胞和胆管细胞之间的相互作用
  • 批准号:
    10494268
  • 财政年份:
    2021
  • 资助金额:
    $ 16.75万
  • 项目类别:
Interactions between neutrophils and cholangiocytes in alcoholic hepatitis
酒精性肝炎中中性粒细胞和胆管细胞之间的相互作用
  • 批准号:
    10646369
  • 财政年份:
    2021
  • 资助金额:
    $ 16.75万
  • 项目类别:
Interactions between neutrophils and cholangiocytes in alcoholic hepatitis
酒精性肝炎中中性粒细胞和胆管细胞之间的相互作用
  • 批准号:
    10874892
  • 财政年份:
    2021
  • 资助金额:
    $ 16.75万
  • 项目类别:
Ca2+ waves in hepatocytes: Mechanisms and effects
肝细胞中的 Ca2 波:机制和作用
  • 批准号:
    10388244
  • 财政年份:
    2018
  • 资助金额:
    $ 16.75万
  • 项目类别:
Ca2+ waves in hepatocytes: Mechanisms and effects
肝细胞中的 Ca2 波:机制和作用
  • 批准号:
    9902430
  • 财政年份:
    2018
  • 资助金额:
    $ 16.75万
  • 项目类别:
Molecular regulation of cholestasis in cholangiocytes
胆管细胞胆汁淤积的分子调控
  • 批准号:
    9925220
  • 财政年份:
    2018
  • 资助金额:
    $ 16.75万
  • 项目类别:
Enrichment Program
强化计划
  • 批准号:
    8916082
  • 财政年份:
    2015
  • 资助金额:
    $ 16.75万
  • 项目类别:
Trafficking of the EGF receptor to the nucleus: Mechanisms and Effects
EGF 受体转运至细胞核:机制和作用
  • 批准号:
    8152910
  • 财政年份:
    2012
  • 资助金额:
    $ 16.75万
  • 项目类别:

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