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: 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
• 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

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学变化基本缺乏了解。这伊萨由于技术上的困难，阻碍了肝活检组织的检查超出了观察到的形态学变化。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。本申请的目的是确定：1）酒精性肝炎中细胞周期阻滞的机制; 2）窦状隙中巨噬细胞的病理生理学 酒精性肝炎中的作用，包括它们在阻塞肝窦血流引起肝细胞缺氧损伤中的作用; 3）酒精性肝炎中肝细胞气球样变性的机制。由于新技术的发展，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形态测量，这些问题现在可以直接在肝活检组织上得到回答。核心假设是细胞周期停滞、气球肝细胞的表观遗传转化和由巨噬细胞引起的窦状隙阻塞引起的小叶中心肝细胞缺氧，联合收割机联合损伤肝细胞，导致酒精性肝炎的功能丧失和肝功能衰竭。在气球样肝细胞中发展的表观遗传变化导致癌前肝细胞形成和肝细胞癌的发展。这一假设是根据申请人实验室提供的初步数据提出的。这项研究的基本原理是，了解酒精性肝炎肝损伤的基本机制将促进新的和更有效的治疗酒精性肝炎，其中细胞周期 停滞被逆转为正常;阻塞的巨噬细胞从窦状隙中被去除，并且防止了气球细胞变性。在强有力的初步数据的指导下，将通过追求三个具体目标来检验这一假设。1)确定由p21诱导引起的细胞周期停滞的机制; 2）确定导致小叶中心缺氧损伤的4种类型的阻塞窦状隙的巨噬细胞，以及3）确定表征肝细胞气球细胞变性的表观遗传转化。该方法是创新的，主要是因为它利用了在申请人的实验室中开发的上述新技术，首次能够直接研究来自酒精性肝炎患者的肝活检。拟议的研究是重要的，因为预计当酒精性肝炎所涉及的机制被理解时，将有可能设计出挽救生命的疗法，节省目前用于治疗酒精性肝炎的主要成本。