Role of macrophage evolution in hepatic adaptation to alcohol.

巨噬细胞进化在肝脏适应酒精中的作用。

基本信息

  • 批准号:
    10292924
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-10-01 至 2023-09-30
  • 项目状态:
    已结题

项目摘要

PROJECT TITLE: Role of macrophage evolution in hepatic adaptation to alcohol PROJECT SUMMARY / ABSTRACT Acute alcoholic hepatitis (AH) is a severe inflammatory liver disease triggered by binge drinking. The disease has a 30-day mortality of approximately 20%. One of the most striking features of AH is that it affects only a small minority of heavy drinkers suggesting that most individuals are protected from developing alcoholic liver disease by as yet unknown mechanisms. We have recently shown that alcohol exposure in mice causes early changes in liver macrophage (MΦ) populations with a loss of up to 50% of Kupffer cells and entry of infiltrating macrophages. By 10 days, Kupffer cell numbers are restored but their gene expression patterns have become more like anti-inflammatory M2 macrophages. By 35 days of alcohol exposure, the hepatic MΦ gene expression pattern changes further with a decrease in some of the classic M2 markers and the development of a gene expression pattern associated with a restorative MΦ phenotype. The macrophage population changes correlate with changes in the sensitivity of the liver to a challenge with LPS. We hypothesize that the “lost” Kupffer cells are rapidly replaced by “adaptive” macrophages leading to a state in which liver inflammation is minimal. This adaptive macrophage formation requires Kupffer cell-derived apoptotic bodies and Th2 cytokines such as IL4 and IL13. The balance of pro-and anti-inflammatory MΦs and the nature of the hepatic adaptive MΦ populations change over time so that with prolonged alcohol exposure, adaptation can be lost and liver inflammation can occur. Better understanding of the nature of the adaptive macrophages and the factors that lead to their formation, maintenance and loss would provide new approaches for the therapy of alcoholic liver disease. We will explore this hypothesis with the following specific aims: Aim 1: To determine the origins, gene expression patterns and functional properties of the mouse liver MΦ subtypes that appear after alcohol exposure. We will use lineage tracing techniques and single cell RNA sequencing to define the origin and diversity of the macrophage populations present. We will then isolate the adaptive macrophage populations to determine their functional properties both in vivo and in vitro. Aim 2: To define the signals responsible for production and maintenance of alcohol adaptive MΦ populations. We will examine the role of specific apoptotic body receptors, the impact of different sources of apoptotic bodies, timing of apoptotic body formation within the liver, and the role of hepatocyte derived factors in the formation of adaptive macrophage populations. Aim 3: To identify macrophage/monocyte populations that contribute to alcohol adaptation in humans. These experiments will leverage the mouse findings made in the first two aims to identify alcohol adaptive macrophage populations in humans. This will be done by immunohistochemical analysis of macrophages in liver autopsy specimens from non-drinkers and chronic alcohol drinkers without liver disease, and liver explants from patients with alcoholic hepatitis. These will be compared to circulating blood monocytes in these patient groups and finally will be compared with macrophages isolated from liver transplant explants of patients with alcoholic cirrhosis and cirrhosis due to etiologies unrelated to alcohol. These studies will enhance our knowledge of how macrophage phenotype changes protect the liver from alcohol, will identify the signals responsible for these changes and will define which changes protect humans from alcoholic liver disease. The long-range goal of this research is to develop macrophage directed therapies to modulate the course of alcoholic hepatitis and enhance anti- inflammatory and tissue restorative effects in a wide range of inflammatory liver diseases.
项目名称:巨噬细胞进化在肝脏适应酒精中的作用 项目总结/摘要 急性酒精性肝炎(AH)是一种由酗酒引发的严重炎症性肝病。疾病 30天内的死亡率约为20% AH最显著的特点之一是它只影响一个 少数重度饮酒者表明大多数人不会患上酒精肝 疾病的发病机制尚不清楚。我们最近的研究表明,小鼠体内的酒精暴露会导致早期 肝脏巨噬细胞(MΦ)群体的变化,枯否细胞损失高达50%,浸润细胞进入 巨噬细胞10天后,库普弗细胞数量恢复,但它们的基因表达模式变得 更像是抗炎的M2巨噬细胞酒精暴露35天,肝脏MΦ基因表达 随着一些经典的M2标记的减少和基因的发展,模式进一步改变。 与恢复性MΦ表型相关的表达模式。巨噬细胞数量的变化与 肝脏对LPS刺激的敏感性发生变化。我们假设“丢失的”库普弗细胞 被“适应性”巨噬细胞迅速取代,导致肝脏炎症最小的状态。这 适应性巨噬细胞的形成需要枯否细胞衍生的凋亡小体和Th 2细胞因子如IL 4 IL13。促炎和抗炎MΦ的平衡和肝脏适应性MΦ群的性质 随着时间的推移而变化,因此随着长期酒精暴露,适应能力可能会丧失,肝脏炎症可能会 发生.更好地了解适应性巨噬细胞的性质以及导致其 其形成、维持和丢失为酒精性肝病的治疗提供了新的途径。我们 我将探讨这一假设与以下具体目标:目的1:确定起源,基因表达 小鼠肝脏MΦ亚型在酒精暴露后出现的模式和功能特性。 我们将使用谱系追踪技术和单细胞RNA测序来确定这些基因的起源和多样性。 存在巨噬细胞群体。然后,我们将分离适应性巨噬细胞群体,以确定其 在体内和体外的功能特性。目标2:确定负责生产和 维持酒精适应性MΦ群体。我们将研究特定的凋亡小体的作用, 受体,不同来源的凋亡小体的影响,肝内凋亡小体形成的时间, 以及肝细胞衍生因子在适应性巨噬细胞群体形成中的作用。目标3: 鉴定巨噬细胞/单核细胞群体有助于人类酒精适应。这些 实验将利用前两个实验中的小鼠发现, 人类的人口。这将通过肝脏尸检中巨噬细胞的免疫组织化学分析来完成 来自非饮酒者和无肝病的慢性饮酒者的标本,以及来自患者的肝脏外植体 酒精性肝炎这些将与这些患者组中的循环血液单核细胞进行比较, 将与从酒精性肝硬化患者的肝移植外植体中分离的巨噬细胞进行比较, 与酒精无关的病因引起的肝硬化。这些研究将增强我们对巨噬细胞如何 表型变化保护肝脏免受酒精的影响,将识别负责这些变化的信号,并将 确定哪些变化可以保护人类免受酒精性肝病的影响。这项研究的长期目标是 开发巨噬细胞定向疗法,以调节酒精性肝炎的进程,并增强抗 在广泛的炎症性肝病中的炎症和组织恢复作用。

项目成果

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STEVEN A WEINMAN其他文献

STEVEN A WEINMAN的其他文献

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{{ truncateString('STEVEN A WEINMAN', 18)}}的其他基金

Kansas Center for Metabolism and Obesity REsearch (KC-MORE) - Administrative Core
堪萨斯代谢和肥胖研究中心 (KC-MORE) - 行政核心
  • 批准号:
    10598013
  • 财政年份:
    2022
  • 资助金额:
    --
  • 项目类别:
Role of macrophage evolution in hepatic adaptation to alcohol.
巨噬细胞进化在肝脏适应酒精中的作用。
  • 批准号:
    10515320
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Role of macrophage evolution in hepatic adaptation to alcohol.
巨噬细胞进化在肝脏适应酒精中的作用。
  • 批准号:
    10045504
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Monocyte regulation in human alcoholic hepatitis.
人类酒精性肝炎中的单核细胞调节。
  • 批准号:
    9566962
  • 财政年份:
    2017
  • 资助金额:
    --
  • 项目类别:
Monocyte regulation in human alcoholic hepatitis.
人类酒精性肝炎中的单核细胞调节。
  • 批准号:
    9373415
  • 财政年份:
    2017
  • 资助金额:
    --
  • 项目类别:
Pilot Grants Program
试点资助计划
  • 批准号:
    10013242
  • 财政年份:
    2016
  • 资助金额:
    --
  • 项目类别:
Mechanisms of Liver Injury by Hepatitis C and Alcohol
丙型肝炎和酒精损伤肝的机制
  • 批准号:
    7928541
  • 财政年份:
    2009
  • 资助金额:
    --
  • 项目类别:
Mechanisms of Liver Injury by Hepatitis C and Alcohol
丙型肝炎和酒精损伤肝的机制
  • 批准号:
    7907385
  • 财政年份:
    2000
  • 资助金额:
    --
  • 项目类别:
Role of alcohol adapted Kupffer cells in the progression and resolution of ALD
酒精适应库普弗细胞在 ALD 进展和消退中的作用
  • 批准号:
    10660796
  • 财政年份:
    2000
  • 资助金额:
    --
  • 项目类别:
Mechanisms of Liver Injury by Hepatitis C and Alcohol
丙型肝炎和酒精损伤肝的机制
  • 批准号:
    8812759
  • 财政年份:
    2000
  • 资助金额:
    --
  • 项目类别:

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