STUDY OF KSHV REACTIVATION AND PATHOGENESIS

KSHV 再激活和发病机制的研究

• 批准号: 6350451
• 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/6350451
• 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.

Kaposi综合征（KS）是混合细胞组成的多灶性血管肿瘤，是获得性免疫缺陷综合征（AIDS）患者中最常见的肿瘤。 Kaposi组的新成员是Kaposi的肉瘤相关疱疹病毒（KSHV）或人类疱疹病毒8（HHV8），在KS的基于KS体腔淋巴瘤和某些形式的Castleman疾病中一直始终如一地鉴定出来。尽管仍然有限，但目前可用的数据提供了令人信服的证据，表明KSHV是KS的长期传染病。提出的研究旨在研究新鉴定的KSHV K15对细胞信号的调节 - 位于等同于编码爱泼斯坦Barr病毒LMP2A（EBV）的基因的位置，KSHV包含一个独特的开放阅读框架，称为K15。尽管K15与LMP2A没有同源性，但两种蛋白质都包含相似的结构组织，包括多个跨膜跨度域和信号传递模块。我们假设K15调节细胞信号转导活性，以改变K15的细胞信号转导活性，以调节病毒裂解的活化并有助于对细胞生长控制的放松管制。最初的研究将集中于在各种KSHV感染的细胞和肿瘤组织中K15基因表达的表征。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。为了定义K15在病毒裂解的重新激活和转化中的作用，我们建议测试K15是否能够在EBV LMP2A-胞质细胞系（LCLS）中替换LMP2A功能（LCLS）和疱疹病毒Saimiri上下文中的尖端功能。拟议的研究将增加我们对KSHV潜伏期和发病机理的分子机制的理解。