STUDY OF KSHV REACTIVATION AND PATHOGENESIS

KSHV 再激活和发病机制的研究

• 批准号: 6628475
• 负责人: Jae U Jung
• 金额: $ 27.54万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-01 至 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6628475
• 关键词: B lymphocyte; Callithricidae; Epstein Barr virus; Herpesvirus saimiri; Kaposi's sarcoma; biological signal transduction; cell line; circular DNA; clinical research; genetic promoter element; human herpesvirus 8; human subject; in situ hybridization; latent virus infection; leukocyte activation /transformation; lymphoma; northern blottings; nucleic acid repetitive sequence; pathologic process; polymerase chain reaction; viral carcinogenesis; virus genetics; virus protein

Kaposi's syndrome (KS) is a multifocal vascular tumor of mixed cellular composition that is the most common neoplasm in patients with acquired immunodeficiency syndrome (AIDS). A new member of the herpesvirus group, Kaposi's sarcoma-associated herpesvirus (KSHV) or human herpesvirus 8 (HHV8), has been consistently identified in KS body cavity- based lymphoma and some forms of Castleman's disease. Although still limited, the presently available data provide compelling evidence that KSHV is the long-sought infectious cause of KS. The proposed research is directed toward investigating modulation of cellular signaling by a newly identified KSHV K15 - At a position equivalent to the gene encoding the LMP2A of Epstein Barr virus (EBV), KSHV contains a distinct open reading frame called K15. Although K15 does not exhibit homology to LMP2A, both proteins contain similar structural organization including multiple transmembrane spanning domains and signal transducing modules. We hypothesize that K15 modulates cellular signal transducing activity to that K15 alters cellular signal transducing activity to regulate viral lytic reactivation and to contribute to deregulation of cell growth control. Initial research will focus on the characterization of expression of K15 gene in various KSHV infected cells and tumor tissues. Detailed biochemical studies on the role of K15 will include mutational analysis, effect on cellular signal transduction, and identification of cellular partners. To define the role of K15 in viral lytic reactivation and transformation, we propose to test whether K15 is capable of substituting for the LMP2A function in EBV LMP2A- lymphoblastoid cell lines (LCLs) and for the Tip function in context of herpesvirus saimiri. The proposed studies will increase our understanding of molecular mechanism of the KSHV latency and pathogenesis.

卡波西综合征 (KS) 是一种混合细胞成分的多灶性血管肿瘤，是获得性免疫缺陷综合征 (AIDS) 患者中最常见的肿瘤。疱疹病毒组的一个新成员，卡波西肉瘤相关疱疹病毒 (KSHV) 或人类疱疹病毒 8 (HHV8)，已在 KS 体腔淋巴瘤和某些形式的卡斯尔曼病中得到一致鉴定。尽管仍然有限，但目前可用的数据提供了令人信服的证据，证明 KSHV 是长期以来寻找的 KS 感染原因。拟议的研究旨在研究新发现的 KSHV K15 对细胞信号传导的调节——在与编码 Epstein Barr 病毒 (EBV) LMP2A 的基因相当的位置，KSHV 包含一个独特的开放阅读框，称为 K15。尽管 K15 与 LMP2A 不具有同源性，但这两种蛋白都包含相似的结构组织，包括多个跨膜结构域和信号转导模块。我们假设 K15 调节细胞信号转导活性，K15 改变细胞信号转导活性以调节病毒裂解再激活并有助于解除细胞生长控制的调节。初步研究将集中于各种 KSHV 感染细胞和肿瘤组织中 K15 基因表达的特征。关于 K15 作用的详细生化研究将包括突变分析、对细胞信号转导的影响以及细胞伴侣的鉴定。为了确定 K15 在病毒裂解再激活和转化中的作用，我们建议测试 K15 是否能够替代 EBV LMP2A- 淋巴母细胞系 (LCL) 中的 LMP2A 功能以及疱疹病毒 saimiri 中的 Tip 功能。拟议的研究将增加我们对 KSHV 潜伏期和发病机制的分子机制的理解。