Determining the mechanism of miR-122 regulation of HCV translation

HCV引起肝脏疾病和癌症，并且是北美肝衰竭和肝移植的主要原因。细胞内的小分子RNA（microRNA，miRNA）调节细胞内基因的表达。肝脏特异性miRNA miR-122调节脂质和胆固醇代谢以及细胞分化，并且miR-122的失调与肝癌有关。 有趣的是，miR-122还调节HCV在感染细胞中生长的效率。miR-122的拮抗剂抑制HCV感染，最近的II期试验表明，它们在治疗人类HCV感染方面是安全有效的。然而，我们目前还不知道miR-122如何促进HCV复制。miR-122和HCV基因组之间的直接相互作用是必需的，但这如何促进病毒复制尚不清楚。在我们的研究中，我们正在努力确定参与miR-122活性的病毒和细胞组分，以便我们可以更多地了解miR-122活性的机制。我们发现一种非常规形式的miR-122可能具有促进HCV的功能，并向我们表明细胞中可能存在不同的miR-122群体。 我们建议确认独特的miR-122形式的身份和活性。 我们还鉴定了两种参与miR-122活性的宿主细胞蛋白，Ago2和DDX6。 Ago2和DDX6都是正常miRNA调节宿主基因的机制所必需的，我们的目标是确定它们在促进HCV复制中的特定作用。 随着这些研究的完成，我们将构建miR-122激活HCV感染机制的模型。这些信息还将提供对miR-122在调节肝细胞翻译中的作用的深入了解。

HCV causes liver disease and cancer, and is a major cause of liver failure, and liver transplantation in North America. Cellular small RNAs, known as microRNAs (miRNA), regulate cellular gene expression. A liver specific miRNA, miR-122, regulates lipid and cholesterol metabolism, and cellular differentiation, and dis-regulation of miR-122 has been linked to liver cancer. Interestingly, miR-122 also modulates the efficiency by which HCV grows in infected cells. Antagonists of miR-122 inhibit HCV infections, and recent phase II trials showed that they are safe and effective in treating HCV infections in humans. However, we currently do not know how miR-122 promotes HCV replication. A direct interaction between miR-122 and the HCV genome is required, but how this promotes virus replication is unknown. In our research we are striving to determine the viral and cellular components that are involved in the activity of miR-122 so that we may learn more about the mechanism of miR-122 activity. We have found that an unconventional form of miR-122 may function to promote HCV, and suggests to us that different populations of miR-122 may exist in cells. We propose to confirm the identity and activity of the unique miR-122 form. We have also identified two host cellular proteins that are involved in miR-122 activity, Ago2 and DDX6. Both Ago2 and DDX6 are required for the mechanism by which normal miRNA regulate host genes, and our goals are to determine their specific roles in promoting HCV replication. With the completion of these studies we will construct a model for the mechanism of miR-122 activation of HCV infections. The information will also provide insight into the role of miR-122 in modulating translation in liver cells.