JC Virus and Human Colorectal Neoplasia

描述（由申请人提供）：JCV是一种多瘤病毒，基本上可以感染所有人群。多瘤病毒的特点是具有t抗原（T-Ag）基因，该基因编码一种有效的转化蛋白。尽管我们所有人都接触过这种病毒，而且大多数人长期携带这种病毒，但它通常处于休眠或潜伏状态。多瘤病毒（包括BK病毒和SV40）具有复杂的生命周期，它们可以溶解（复制病毒粒子并杀死宿主细胞）、致癌（有或没有整合，并诱发癌症）或保持潜伏。此外，将JCV注射到啮齿类动物或猴子的大脑中可以诱发癌症。我们假设JCV具有诱导人类结直肠癌（CRC）的能力，我们发现近90%的人类CRC含有这种病毒，其中一半表达T-Ag。重要的是，我们可以在几种体外结肠上皮细胞模式中诱导染色体不稳定性（CIN），这使我们能够详细研究这些转化相关的过程。该应用提出了免疫学研究，以确定特异性细胞介导的免疫反应是否使JCV处于潜伏状态。我们将通过研究患有结直肠腺瘤和癌的个体来验证细胞介导免疫缺陷与JCV作为一种致瘤病毒的出现有关的假设。我们还将检验儿童时期暴露于JCV与家族性腺瘤性息肉病儿童性腺瘤性息肉的出现有关的假设。其次，我们可以通过转染JCV全基因组或仅转染JCV T-Ag基因在两种二倍体CRC细胞模型中诱导CIN。通过将JCV T-Ag基因转染到接近正常的结肠上皮细胞中，我们已经将它们转化为在裸鼠体内形成肿瘤的细胞系。这为我们研究CIN早期转化的分子生物学和体外发育提供了一个模型。同样，我们发现通过转染JCV T-Ag可以在一些非CIMP的CRC细胞系中诱导CIMP。因此，我们可以利用JCV诱导CRC中两个最基本的事件，并可以概括这些早期畸变的演变，以研究CIN和CIMP出现的步骤。本研究的广泛和长期目标是确定接种JCV疫苗是否是预防结直肠癌的合理方法。

DESCRIPTION (provided by applicant): JCV is a polyomavirus that essentially infects all human populations. Polyomaviruses are characterized by virtue of a T-antigen (T-Ag) gene, which encodes a potent transforming protein. In spite of the fact that all of us have been exposed to and most chronically carry this virus, it usually remains dormant or latent. Polyomaviruses (which include BK Virus and SV40) have complex life cycles in which they can be lytic (replicate virions and kill the host cell), become oncogenic (with or without integration, and induce cancer), or remain latent. Moreover, JCV can induce cancer when injected into the brains of rodents or monkeys. We hypothesize that JCV has the capability of inducing colorectal cancer (CRC) in humans, and we have found that nearly 90% of human CRCs harbor this virus, half of which express the T-Ag. Importantly, we can induce chromosomal instability (CIN) in several in vitro colonic epithelial cell modes, which permit us to study these transformation-associated processes in detail. This application proposes immunological studies to determine whether specific cell-mediated immune responses keep JCV in a latent state. We will test the hypothesis that a defect in cell mediated immunity is associated with the emergence of JCV as an oncogenic virus by studying individuals who have developed colorectal adenomas and carcinomas. We will also test the hypothesis that exposure to JCV in childhood is associated with the appearance of adenomatous polyps in children with familial adenomatous polyposis. Second, we can induce CIN in two diploid CRC cell models by transfecting either the full JCV genome or just the JCV T-Ag gene. By transfecting the JCV T-Ag gene into near-normal colon epithelial cells, we have transformed them into a cell line that forms tumors in nude mice. This provides us with a model to study the molecular biology of early transformation, and the development of CIN in vitro. Similarly, we have found that we can induce CIMP in some non-CIMP CRC cell lines by transfecting JCV T-Ag. Therefore, we can induce the two most fundamental events in CRC using JCV, and can recapitulate the evolution of these earliest aberrations to study the steps by which CIN and CIMP emerge. It is the broad, long-term aim of this research to determine whether vaccination against JCV is a reasonable approach to the prevention of CRC. PUBLIC HEALTH RELEVANCE: This project tests the hypothesis that the common human polyomavirus, JC virus can induce the fundamental changes that are required for colorectal neoplasia to develop. It is the long-term aim of this project to determine whether we should develop a vaccine that will prevent primary infection by JC virus, and prevent the occurrence of colorectal cancer.