JC Virus and Human Colorectal Neoplasia

描述（由申请方提供）：JCV是一种多瘤病毒，基本上感染所有人群。多瘤病毒的特征在于T抗原（T-Ag）基因，其编码有效的转化蛋白。尽管我们所有人都接触过这种病毒，而且大多数人都长期携带这种病毒，但它通常处于休眠状态或潜伏状态。多瘤病毒（包括BK病毒和SV 40）具有复杂的生命周期，其中它们可以裂解（复制病毒粒子并杀死宿主细胞），致癌（有或没有整合，并诱导癌症）或保持潜伏。此外，当注射到啮齿动物或猴子的大脑中时，JCV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，并且我们发现近90%的人类CRC携带这种病毒，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过程。本申请提出了免疫学研究以确定特异性细胞介导的免疫应答是否使JCV保持在潜伏状态。我们将通过研究患有结直肠腺瘤和癌的个体来检验细胞介导的免疫缺陷与JCV作为致癌病毒的出现相关的假设。我们还将检验儿童期暴露于JCV与家族性腺瘤性息肉病儿童腺瘤性息肉的出现相关的假设。第二，我们可以通过切除完整的JCV基因组或仅切除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中形成肿瘤的细胞系。这为我们研究早期转化的分子生物学和CIN的体外发展提供了一个模型。类似地，我们已经发现我们可以通过抑制JCV T-Ag在一些非CIMP CRC细胞系中诱导CIMP。因此，我们可以使用JCV诱导CRC中两个最基本的事件，并且可以概括这些最早期畸变的演变，以研究CIN和CIMP出现的步骤。本研究的广泛、长期目标是确定接种JCV疫苗是否是预防CRC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.