Alcohol Alters Hepatic Immune Function: Role of the Asialoglycoprotein Receptor

酒精改变肝脏免疫功能:去唾液酸糖蛋白受体的作用

基本信息

  • 批准号:
    8244030
  • 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:
    2011
  • 资助国家:
    美国
  • 起止时间:
    2011-10-01 至 2015-09-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): ABSTRACT Chronic alcohol consumption is associated with the development of alcoholic liver disease (ALD), a major cause of morbidity and mortality in the U.S. including our Veteran population. Prominent features of ALD include ethanol-mediated cellular alterations, steatosis and hepatic inflammation; however, a comprehensive understanding of the mechanisms involved remains incomplete. It has previously been shown that hepatocellular protein trafficking pathways were found to be highly susceptible to the detrimental effects of alcohol. In particular, our laboratory identified multiple ethanol-induced alterations in the process of receptor- mediated endocytosis (RME) and more specifically, we discovered that ethanol treatment resulted in marked impairments in the function of the hepatocyte-specific asialoglycoprotein (ASGP) receptor. However, translating the observed alterations in ASGP receptor function to the incidence and/or severity of ALD remains uncharacterized. Recently it has been suggested that the recognition and subsequent regulation of immune cells could be a potential physiological role of the ASGP receptor. In preliminary studies for this proposal, we have demonstrated that the ASGP receptor specifically binds to lymphocytes and that the absence of the hepatic receptor results in the accumulation of intrahepatic T cells and enhanced liver injury. Therefore, we propose that the ASGP receptor has a role in the regulation of immune cells in the healthy liver and that ethanol-induced impairments in ASGP receptor function can result in increased liver injury caused by T cell- mediated events. The overall working hypothesis of this study is that ASGP receptors establish connections between hepatocytes and activated T lymphocytes (immune cells that are known to accumulate following liver injury) which facilitate the beneficial removal of potentially damaging T cells. Furthermore, as a consequence of ethanol-mediated alterations to the ASGP receptor, altered clearance of T cells occurs leading to abnormal lymphocyte accumulation, events that could contribute the development of hepatitis and the progression of ALD. We will address these hypotheses with the following specific aims: In initial studies, the recognition and binding of T lymphocytes to the hepatocyte ASGP receptor will be characterized in vitro. Next, lymphocyte clearance mechanisms (phagocytosis and/or T cell death mechanisms) triggered as a result of ASGP receptor- mediated hepatocyte-lymphocyte interactions will be analyzed. And finally, in vivo studies are proposed to demonstrate the importance of altered or absent functional ASGP receptors in the development of immune cell related liver injury using models of ethanol administration along with an ASGP receptor knockout mouse treated with inducers T cell-mediated hepatitis. Information gained from this research can significantly impact our understanding of how hepatocyte-lymphocyte interactions maintain proper T cell homeostasis in the liver and how impairments in such interactions can lead to enhancements in liver disease. Overall, this work aims to establish and characterize the role of the hepatic ASGP receptor in immune regulation and whether the alterations of this proce
描述(由申请人提供):

项目成果

期刊论文数量(0)
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BENITA L. MCVICKER其他文献

BENITA L. MCVICKER的其他文献

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{{ truncateString('BENITA L. MCVICKER', 18)}}的其他基金

ACORN: BioCore
橡子:生物核心
  • 批准号:
    10526255
  • 财政年份:
    2023
  • 资助金额:
    --
  • 项目类别:
Alcohol-sensitized macrophages enhance colorectal carcinoma metastasis in the liver
酒精敏感性巨噬细胞增强结直肠癌肝转移
  • 批准号:
    10427229
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Development of delivery methods for combination microRNA treatment of alcohol-associated liver disease
开发联合 microRNA 治疗酒精相关性肝病的递送方法
  • 批准号:
    10442687
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Alcohol-sensitized macrophages enhance colorectal carcinoma metastasis in the liver
酒精敏感性巨噬细胞增强结直肠癌肝转移
  • 批准号:
    10265327
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Development of delivery methods for combination microRNA treatment of alcohol-associated liver disease
开发联合 microRNA 治疗酒精相关性肝病的递送方法
  • 批准号:
    10676945
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Alcohol Alters Hepatic Immune Function: Role of the Asialoglycoprotein Receptor
酒精改变肝脏免疫功能:去唾液酸糖蛋白受体的作用
  • 批准号:
    8391632
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:
Alcohol Alters Hepatic Immune Function: Role of the Asialoglycoprotein Receptor
酒精改变肝脏免疫功能:去唾液酸糖蛋白受体的作用
  • 批准号:
    8598019
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:
Alcohol & FAS-Mediated Apoptosis in Polarized Liver Cell
酒精
  • 批准号:
    7045785
  • 财政年份:
    2006
  • 资助金额:
    --
  • 项目类别:
Alcohol & FAS-Mediated Apoptosis in Polarized Liver Cell
酒精
  • 批准号:
    7564111
  • 财政年份:
    2006
  • 资助金额:
    --
  • 项目类别:
Alcohol & FAS-Mediated Apoptosis in Polarized Liver Cell
酒精
  • 批准号:
    7337638
  • 财政年份:
    2006
  • 资助金额:
    --
  • 项目类别:

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