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

批准号：
8428031
负责人：
SAMUEL William FRENCH
金额：
$ 21.01万
依托单位：
LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-10 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8428031
关键词：
26S proteasome Alcoholic Hepatitis Alcoholic Liver Diseases Alcohols Animals Apoptosis Applications Grants Area Bile fluid Biopsy Specimen Blood flow California Cell Communication Cell Cycle Arrest Cell Cycle Progression Cell Hypoxia Cells Cellular Morphology Cost Savings Data Development Diet Discontinuous Capillary Dissection Epigenetic Process Fostering Functional disorder Gene Expression Gene Silencing Genomic Instability Goals Hepatocyte Hospitalization Human Hypoxia Individual Injury Knowledge Laboratories Lasers Lead Life Liver Liver Failure Liver parenchyma Measurement Mission Molecular Morbidity - disease rate Natural regeneration Normal Cell Obstruction Outcome Pathogenesis Patients Play Population Primary carcinoma of the liver cells Principal Investigator Proteasome Inhibition Proteins Public Health Research Role Stem cells Techniques Testing Time Tissues Translational Research base cell injury cell type cost cytokine design effective therapy improved injured innovation liver biopsy liver function liver injury liver transplantation loss of function macrophage molecular pathology mortality mouse model new technology prevent problem drinker public health relevance response therapy design ubiquitin ligase

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）：对于肝活检组织水平上酒精性肝炎的分子病理学变化，人们根本缺乏了解。这是技术困难的结果，技术困难阻碍了对肝活检组织的检查，超出了观察到的形态变化。最近，PI 实验室开发了一些技术，现在可以检查酒精性肝炎患者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联。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制； 2) 血窦中巨噬细胞的病理生理学在酒精性肝炎中，包括其阻碍肝窦血流，导致肝细胞缺氧损伤的作用； 3）酒精性肝炎肝细胞球囊细胞变性的机制。由于激光捕获解剖和位于不同细胞群中的蛋白质的荧光强度形态测量等新技术的发展，这些问题现在可以直接在肝活检组织上得到解答。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巨噬细胞阻塞肝窦引起的小叶中心肝细胞缺氧，共同损伤肝细胞，导致酒精性肝炎的功能丧失和肝衰竭。气球状肝细胞中发生的表观遗传变化导致肿瘤前肝细胞形成和肝细胞癌的发展。该假设是根据申请人实验室产生的初步数据制定的。拟议研究的基本原理是，了解酒精性肝炎肝损伤的基本机制将促进新的、更有效的酒精性肝炎治疗方法，其中细胞周期逮捕恢复正常；从血窦中去除阻塞性巨噬细胞，并防止球囊细胞变性。在强有力的初步数据的指导下，这一假设将通过追求三个具体目标进行检验。 1）确定p21诱导引起细胞周期停滞的机制； 2) 确定阻碍小叶中心缺氧损伤的血窦的 4 种巨噬细胞，以及 3) 确定表征肝细胞球囊细胞变性的表观遗传转化。该方法之所以具有创新性，主要是因为它利用了申请人实验室开发的上述新技术，首次能够对酒精性肝炎患者的肝活检进行直接研究。拟议的研究意义重大，因为预计当了解酒精性肝炎涉及的机制时，将有可能设计出挽救生命的疗法，并节省目前用于治疗酒精性肝炎的大量成本。