Pathogenesis of ground glass cells in hepatitis B

描述：（改编自研究者摘要）：B型肝炎病毒 (HBV)引起慢性肝炎、肝硬化和肝细胞癌（HCC）， 在非洲裔美国人和亚洲人等少数民族中尤其常见 美国人HBV引起HCC的机制尚不清楚，但很可能 HCC是由特异性病毒因素和非特异性突变引起的 因为细胞不断更新一个候选病毒因子是大表面 蛋白，因为该蛋白在转基因小鼠中的表达导致HCC。我们 最近表明，大的表面蛋白可以激活细胞基因， 转录水平，显然是通过形成非分泌颗粒， 内质网（ER）和激活ER应激。进一步的初步 数据表明，大的表面蛋白质可能通过以下方式导致细胞死亡： 凋亡由于肝细胞内含有大的表面蛋白颗粒， ER（“毛玻璃细胞”）见于慢性胰腺炎患者的肝脏， B型肝炎，我们的研究结果指出了一个特定的机制， HCC。然而，在受感染的肝脏中形成毛玻璃细胞的原因是 目前仍不清楚.对于这个项目的下一个周期，我们建议研究 毛玻璃细胞形成的上游和下游。第一、 我们希望验证我们的假设，即病毒基因组的突变可以导致 毛玻璃细胞，并确定是否有两种常见的自然发生的病毒 突变体可在转基因小鼠中引起毛玻璃细胞和HCC。二是 将从人类毛玻璃细胞中克隆出HBV基因组， 可能导致毛玻璃细胞形成的其他突变。 第三，我们将确定多大的表面蛋白导致细胞死亡， 无论是通过细胞凋亡。我们还将确定是否有增加 转基因小鼠毛玻璃细胞凋亡，并寻找激活 具有毛玻璃细胞的人类肝脏中的凋亡途径。这些实验 应该为乙型肝炎病毒引起肝脏的机制提供新的见解 疾病

DESCRIPTION: (Adapted from the Investigator's abstract): Hepatitis B virus (HBV) causes chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC), and is especially common among minorities such as African Americans and Asian Americans. The mechanism by which HBV causes HCC is unclear, but it is likely that HCC results from both specific viral factors and non-specific mutagenesis due to constant cell turnover. One candidate viral factor is the large surface protein, since expression of this protein in transgenic mice results in HCC. We have recently shown that large surface protein can activate cellular genes at the transcriptional level, apparently by forming non-secretable particles in the endoplasmic reticulum (ER) and activating ER stress. Further preliminary data indicate that large surface protein causes cell death, probably by apoptosis. Since hepatocytes containing large surface protein particles within the ER ("ground glass cells") are seen in the livers of people with chronic hepatitis B, our results point to a specific mechanism whereby HBV may cause HCC. However, the reason for ground glass cell formation in infected livers is still unclear. For the next cycle of this project, we propose to study events both up-stream and down-stream of the formation of ground glass cells. First, we wish to validate our hypothesis that mutations in the viral genome can lead to ground glass cells, and determine if two common naturally occurring viral mutants can cause ground glass cells and HCC in transgenic mice. Second, we will clone out HBV genomes from human ground glass cells, and look for additional mutations that may be responsible for ground glass cell formation. Third, we will determine how large surface protein causes cell death, and whether it is by apoptosis. We will also determine if there is increased apoptosis of ground glass cells in transgenic mice, and look for activation of apoptotic pathways in human livers with ground glass cells. These experiments should give novel insights into the mechanism by which HBV causes liver disease.