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
• 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
• 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/8991280
• 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; Health; 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; response; therapy design; ubiquitin ligase

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）：在肝活检组织水平上，对酒精性肝炎的分子病理变化缺乏基本的了解。这是由于技术上的困难阻碍了对肝活检组织的检查，超出了观察到的形态学变化。最近，PI的实验室开发了一种技术，现在可以检查酒精性肝炎患者肝脏活检中基因表达的变化。长期目标是在分子水平上更好地理解基因表达的变化，并将它们与细胞形态水平相关联。在这个特殊的应用目的是确定，1)酒精性肝炎细胞周期阻滞的机制；2)巨噬细胞在窦内的病理生理