Pathogenesis of ground glass cells in hepatitis B

描述：(改编自调查人员摘要)：乙肝病毒 (乙肝病毒)会导致慢性肝炎、肝硬变和肝细胞癌， 在非裔美国人和亚裔等少数族裔中尤其常见 美国人。乙肝病毒导致肝细胞癌的机制尚不清楚，但很可能 肝细胞癌是由特定病毒因素和非特异性突变共同作用的结果 由于不断的细胞更替。一个可能的病毒因素是巨大的表面 蛋白质，因为在转基因小鼠中表达这种蛋白质会导致肝细胞癌。我们 最近表明，大的表面蛋白可以激活细胞基因在 转录水平，显然是通过在 内质网(ER)和激活内质网应激。进一步的初步调查 数据表明，大型表面蛋白导致细胞死亡，可能是通过 细胞凋亡。由于肝细胞内含有较大的表面蛋白颗粒 内质网(“毛玻璃细胞”)见于慢性阻塞性肺疾病患者的肝脏。 乙肝，我们的结果指出了一种特定的机制，即乙肝病毒可能会导致 肝细胞癌。然而，在感染的肝脏中形成毛玻璃细胞的原因是 仍不清楚。对于这个项目的下一个周期，我们建议研究事件 上游和下游都形成了毛玻璃细胞。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 研磨玻璃细胞，并确定两种常见的自然发生的病毒 突变可导致转基因小鼠的毛玻璃细胞和肝细胞癌。第二，我们 将从人类毛玻璃细胞中克隆出乙肝病毒基因组，并寻找 可能与毛玻璃细胞形成有关的其他突变。 第三，我们将确定大的表面蛋白如何导致细胞死亡，以及 无论是通过细胞凋亡。我们还将确定是否增加了 转基因小鼠磨玻璃细胞的凋亡，并寻找其激活 有毛玻璃细胞的人肝脏中的凋亡途径。这些实验 应该对乙肝病毒引起肝脏的机制有新的见解 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.