ALCOHOLIC HEPATITIS PATHOGENESIS AS DETERMINED FROM HUMAN LIVER TISSUE ANALYSIS

根据人体肝组织分析确定酒精性肝炎发病机制

基本信息

项目摘要

DESCRIPTION (provided by applicant): There is a fundamental lack of understanding about the changes in molecular pathology in alcoholic hepatitis at the liver biopsy tissue level. This isa result of technical difficulties which impede the examination of liver biopsy tissue beyond the morphologic changes observed. Recently techniques have been developed in the PI's laboratory, which now make it possible to examine the changes in gene expression in liver biopsies from patients with alcoholic hepatitis. The long term goal is to better understand the changes in gene expression at the molecular level and to correlate them with the cellular morphology level. The objective in this particular application is to determine, 1) the mechanism of cell cycle arrest in alcoholic hepatitis; 2) the pathophysiology of macrophages in the sinusoids in alcoholic hepatitis including their role in obstructing sinusoidal blood flow causing hypoxic injury to the hepatocytes; 3) the mechanism of balloon cell degeneration of hepatocytes in alcoholic hepatitis. These questions can now be answered directly on liver biopsy tissue due to the development of new technologies such as laser capture dissection and fluorescent intensity morphometric measurements of proteins located in the different cell population. The central hypothesis is that cell cycle arrest, epigenetic transformation of balloon hepatocytes and hypoxia of centrilobular hepatocytes caused by sinusoidal obstruction by macrophages, combine to injure hepatocytes, causing loss of function and liver failure in alcoholic hepatitis. The epigenetic changes that develop in ballooned hepatacytes lead to preneoplastic hepatocyte formation and development of hepatocellular carcinoma. This hypothesis has been formulated on the basis of preliminary data produced in the applicant's laboratory. The rationale for the proposed research is that understanding the fundamental mechanism of liver injury in alcoholic hepatitis will foster new and more effective treatments for alcoholic hepatitis in which cell cycle arrest is reversed to normal; obstructing macrophages are removed from the sinusoids and balloon cell degeneration is prevented. Guided by the strong preliminary data, this hypothesis will be tested by pursuing three specific aims. 1) Determine the mechanism of cell cycle arrest caused by p21 induction; 2) determine the 4 types of macrophages obstructing the sinusoids that cause centrilobular hypoxic injury, and 3) determine the epigenetic transformation that characterizes balloon cell degeneration of hepatocytes. The approach is innovative primarily because it utilizes new technologies described above, developed in the applicant's laboratory, enabling for the first time, the direct study of liver biopsies from patients with alcoholic hepatiis. The proposed research is significant because it is expected that when the mechanisms involved in alcoholic hepatitis are understood it will be possible to design therapies that are life saving with major cost savings that are currently expended in the treatment of alcoholic hepatitis.
描述(由申请人提供):基本上缺乏对肝活检组织水平酒精性肝炎分子病理变化的了解。这是技术困难的结果,这阻碍了观察到的形态变化超出肝活检组织的检查。最近在PI的实验室中开发了技术,现在可以检查酒精性肝炎患者的肝活检中基因表达的变化。长期目标是更好地了解分子水平上基因表达的变化,并将其与细胞形态水平相关。该特定应用的目的是确定,1)酒精性肝炎中细胞周期停滞的机理; 2)正弦体中巨噬细胞的病理生理学 在酒精性肝炎中,包括它们在阻塞正弦血流中的作用,导致肝细胞缺氧损伤; 3)酒精性肝炎中肝细胞的球囊细胞变性机制。这些问题现在可以直接在肝活检组织上回答,这是由于新技术的发展,例如激光捕获解剖和位于不同细胞群中的蛋白质的荧光强度测量。中心假设是细胞周期停滞,球囊肝细胞的表观遗传转化以及由巨噬细胞正弦障碍阻塞引起的中心腔肝细胞的缺氧,结合损伤肝细胞,导致酒精性肝炎的功能和肝衰竭。气囊肝囊肿发生的表观遗传变化导致肝细胞癌的肝细胞形成和发育。该假设是根据申请人实验室中产生的初步数据提出的。拟议的研究的基本原理是了解酒精性肝炎中肝损伤的基本机制将促进对细胞周期的酒精性肝炎的新且更有效的治疗方法 逮捕被逆转到正常;从正弦体中去除阻塞巨噬细胞,并防止球囊细胞变性。在强大的初步数据的指导下,该假设将通过追求三个具体目标来检验。 1)确定由P21诱导引起的细胞周期停滞的机理; 2)确定障碍造成中心腔缺氧损伤的正弦曲线的4种类型,3)确定表观遗传转化的表观遗传转化,该转化表征了肝细胞的球囊细胞变性。这种方法之所以具有创新性,主要是因为它利用了上述新技术,该技术在申请人的实验室中开发,这是第一次,这是对酒精性肝脏患者的肝活检的直接研究。拟议的研究很重要,因为预计当涉及酒精性肝炎的机制时,就可以设计疗法,这些疗法可以通过目前在治疗酒精性肝炎治疗中花费的主要成本节省。

项目成果

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SAMUEL William FRENCH其他文献

SAMUEL William FRENCH的其他文献

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{{ truncateString('SAMUEL William FRENCH', 18)}}的其他基金

ALCOHOLIC HEPATITIS PATHOGENESIS AS DETERMINED FROM HUMAN LIVER TISSUE ANALYSIS
根据人体肝组织分析确定酒精性肝炎发病机制
  • 批准号:
    8991280
  • 财政年份:
    2013
  • 资助金额:
    $ 21.01万
  • 项目类别:
ALCOHOLIC HEPATITIS PATHOGENESIS AS DETERMINED FROM HUMAN LIVER TISSUE ANALYSIS
根据人体肝组织分析确定酒精性肝炎发病机制
  • 批准号:
    8603217
  • 财政年份:
    2013
  • 资助金额:
    $ 21.01万
  • 项目类别:
ALCOHOLIC HEPATITIS PATHOGENESIS AS DETERMINED FROM HUMAN LIVER TISSUE ANALYSIS
根据人体肝组织分析确定酒精性肝炎发病机制
  • 批准号:
    9238635
  • 财政年份:
    2013
  • 资助金额:
    $ 21.01万
  • 项目类别:
CORE--MORPHOLOGY CORE
核心--形态核心
  • 批准号:
    6884956
  • 财政年份:
    2004
  • 资助金额:
    $ 21.01万
  • 项目类别:
RSEARCH PROJECT 2
研究项目2
  • 批准号:
    6884961
  • 财政年份:
    2004
  • 资助金额:
    $ 21.01万
  • 项目类别:
ALCOHOL TRIGGERS DEVELOPMENT OF MALLORY BODIES IN DRUG PRIMED LIVERS
酒精触发药物启动肝脏中马洛里体的发育
  • 批准号:
    6618849
  • 财政年份:
    2002
  • 资助金额:
    $ 21.01万
  • 项目类别:
ALCOHOL TRIGGERS DEVELOPMENT OF MALLORY BODIES IN DRUG PRIMED LIVERS
酒精触发药物启动肝脏中马洛里体的发育
  • 批准号:
    6563236
  • 财政年份:
    2002
  • 资助金额:
    $ 21.01万
  • 项目类别:
ALCOHOL TRIGGERS DEVELOPMENT OF MALLORY BODIES IN DRUG PRIMED LIVERS
酒精触发药物启动肝脏中马洛里体的发育
  • 批准号:
    6410032
  • 财政年份:
    2001
  • 资助金额:
    $ 21.01万
  • 项目类别:
ALCOHOL TRIGGERS DEVELOPMENT OF MALLORY BODIES IN DRUG PRIMED LIVERS
酒精触发药物启动肝脏中马洛里体的发育
  • 批准号:
    6299205
  • 财政年份:
    2000
  • 资助金额:
    $ 21.01万
  • 项目类别:
ALCOHOL TRIGGERS DEVELOPMENT OF MALLORY BODIES IN DRUG PRIMED LIVERS
酒精触发药物启动肝脏中马洛里体的发育
  • 批准号:
    6191992
  • 财政年份:
    1999
  • 资助金额:
    $ 21.01万
  • 项目类别:

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相似海外基金

ALCOHOLIC HEPATITIS PATHOGENESIS AS DETERMINED FROM HUMAN LIVER TISSUE ANALYSIS
根据人体肝组织分析确定酒精性肝炎发病机制
  • 批准号:
    8991280
  • 财政年份:
    2013
  • 资助金额:
    $ 21.01万
  • 项目类别:
ALCOHOLIC HEPATITIS PATHOGENESIS AS DETERMINED FROM HUMAN LIVER TISSUE ANALYSIS
根据人体肝组织分析确定酒精性肝炎发病机制
  • 批准号:
    8603217
  • 财政年份:
    2013
  • 资助金额:
    $ 21.01万
  • 项目类别:
ALCOHOLIC HEPATITIS PATHOGENESIS AS DETERMINED FROM HUMAN LIVER TISSUE ANALYSIS
根据人体肝组织分析确定酒精性肝炎发病机制
  • 批准号:
    9238635
  • 财政年份:
    2013
  • 资助金额:
    $ 21.01万
  • 项目类别:
Alcohol, Proteasome Dysfunction in Liver Injury
酒精、肝损伤中的蛋白酶体功能障碍
  • 批准号:
    7784484
  • 财政年份:
    2009
  • 资助金额:
    $ 21.01万
  • 项目类别:
Alcohol, Proteasome Dysfunction in Liver Injury
酒精、肝损伤中的蛋白酶体功能障碍
  • 批准号:
    7689007
  • 财政年份:
    2009
  • 资助金额:
    $ 21.01万
  • 项目类别:
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