CHARACTERIZATION OF KSHV LANA2

描述：（改编自申请人的摘要）KSHV/HHV 8，第八个人类 疱疹病毒是1993年在申请人的实验室中发现的。与其相关联 三种人类增殖性疾病， 肿瘤形成：Castleman病，Kaposi肉瘤和原发性积液 淋巴瘤（PEL）。这些疾病很少在普通人群中表达， 但在免疫功能低下的KSHV血清阳性个体中很常见， 尤其是艾滋病患者。在过去的一段时间里，研究人员 对病毒基因组进行了测序，发现并鉴定了一些病毒， 可能在KSHV发病机制中发挥作用的基因。他们的研究 集中在肿瘤细胞中表达的潜在病毒基因，这些基因可能 改变宿主细胞调节途径。通过绘制全基因组表达图谱， 确定蛋白质表达模式，他们已经确定了特定的病毒 可能在细胞增殖和预防细胞凋亡中起作用的基因， 原地。最近，他们发现了一个潜在表达的基因， 先前描述的主要潜伏期转录本基因座LT 1的组分，和 LT 2包括v-细胞周期蛋白（0 RF 72）和LANA 1（0 RF 73）。这个1704 bp的拼接基因 编码命名为潜伏相关核抗原（拉娜）2的蛋白质，其 定位于细胞核，并在所有KSHV感染的PEL衍生的 细胞LANA 2与IRF 4转录因子具有结构相似性 存在于B细胞中。这种更新旨在表征这种潜在的蛋白质， 研究其在KSHV相关疾病中的潜在作用。四个具体目标 该建议的主要内容是：1）扩展LANA 2的表征， 对KSHV相关疾病组织中蛋白质的体内表达的影响，2） 扩展他们的初步研究，证明LANA 2介导的上调 CD 23 B细胞活化抗原，也由EB病毒诱导 病毒感染，3）鉴定LANA 2和 参与CD 23转录调节的宿主细胞蛋白，和4） 研究该潜伏病毒基因对细胞周期的潜在作用 调节、凋亡和体外细胞转化。这些研究可能 为CD 23信号转导在肿瘤发生中的生物学作用提供了重要的见解。 淋巴瘤发生和B细胞的疱疹病毒感染。表征 LANA 2也可能有助于未来重要的诊断和治疗 KSHV感染靶点

DESCRIPTION: (Adapted from Applicant's Abstract) KSHV/HHV8, the eighth human herpesvirus, was discovered in applicant's laboratory in 1993. It is associated with three human proliferative diseases ranging from hyperplastic proliferation to neoplasia: Castleman's disease, Kaposi's sarcoma, and primary effusion lymphoma (PEL). These disorders are rarely expressed in the general population, but are common among KSHV seropositive individuals who are immunocompromised, particularly AIDS patients. During the past grant period, the investigators sequenced the viral genome, and discovered and characterized a number of viral genes likely to play a role in KSHV pathogenesis. Their studies have concentrated on latent viral genes expressed in tumor cells that are likely to modify host cell regulatory pathways. By mapping whole genome expression and determining protein expression patterns, they have identified specific viral genes likely to play roles in cell proliferation and prevention of apoptosis in situ. Recently, they have found a latently expressed gene, which is not a component of the previously described major latency transcript locus, LT1 and LT2 encompassing v-cyclin (0RF72) and LANA1 (0RF73). This 1704 bp spliced gene encodes a protein designated latency-associated nuclear antigen (LANA) 2, which is localized to the nucleus and is expressed in all KSHV-infected PEL-derived cells. LANA2 has structural similarities to the IRF4 transcriptional factor present in B cells. This renewal seeks to characterize this latent protein and investigate its potential role in KSHV-related diseases. The four specific aims of this proposal are: 1) to extend the characterization of LANA2 concentrating on the in vivo expression of the protein in KSHV-associated disease tissues, 2) to extend their preliminary studies demonstrating LANA2-mediated upregulation of the CD23 B cell activation antigen, which is also induced by Epstein-Barr virus infection, 3) to identify protein-protein interactions between LANA2 and host cell proteins involved in CD23 transcriptional regulation, and 4) to investigate the potential role of this latent viral gene on cell cycle regulation, apoptosis and in vitro cell transformation. These studies may provide critical insights into the biological role of CD23 signaling in lymphomagenesis and in herpesvirus infection of B cells. Characterization of LANA2 may also contribute to an important future diagnostic and therapeutic target for KSHV infection