Screening of Epstein Barr Virus Replication (RMI)

Epstein Barr 病毒复制 (RMI) 筛选

• 批准号: 6879777
• 负责人: ELLIOTT D KIEFF
• 金额: $ 8.65万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2005-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6879777
• 关键词: B lymphocyte; Epstein Barr virus; drug discovery /isolation; drug screening /evaluation; gene expression; high throughput technology; host organism interaction; immunopharmacology; latent virus infection; plasmids; small molecule; virus antigen; virus genetics; virus infection mechanism; virus replication

DESCRIPTION (provided by applicant): Long term objective is to identify small molecules which can eradicate latent EBV genomes and latently infected cells. The specific objective is to identify chemical candidates that functionally inhibit EBNA1 in cells and in vitro. These molecules could be used to validate the importance of targeting EBNA1 for the elimination of EBV episomes and for halting the growth of latency III infected lymphocytes, in culture or in experimental models. This would provide a compelling model and perhaps a lead compound for approaches to the therapy or prevention of EBV associated PTLD, AIDS associated lymphoma. Although prevalent in all human populations, EBV is an important cause of lymphoma and in immune compromised people Disease (PTLD), various B and T cell Lymphoma (L) and Hodgkin's Lymphoma (HL). EBV replicates in oropharyngeal epithelial cells and establish latency in B lymphocytes. In B cells EBV can establish 3 types of latency. Latency Ill, EBV expresses 6 EB Nuclear antigens (EBNAs) and two integral membrane proteins (LMP1 and 2) and causes lymphocyte proliferation, which is indistinguishable from PTLD. Normally, latency type lll cells are recognized by T lymphocytes and are readily eliminated as immune response develop. Some infected B cells persist in latency type II, wherein only EBNA1, LMP1 and LMP2 are expressed or, in latency type I, wherein only EBAN1 is expressed. EBNA1 is not processed by proteasome pathways and thereby escapes recognition by CD8 cytotoxic T cells. EBNA1 is the only protein required for EBV DNA persistence as extrachromosomal episomes. EBNA1 binds to cognate sequences in oriP and to chromosomes, enabling EBV DNA to be replicated, maintained, transcribed. Therefore, inhibition of EBNA1 function is likely to be efficient way to eradicate EBV infected cells from body.

描述（由申请人提供）：长期目标是确定可以消除潜在EBV基因组和潜在感染细胞的小分子。 具体目标是确定在功能抑制细胞和体外抑制EBNA1的化学候选物。 这些分子可以用来验证靶向EBNA1在消除EBV插发事件中的重要性，并在培养或实验模型中停止潜伏期III感染的淋巴细胞的生长。 这将提供令人信服的模型，也许是一种用于治疗或预防EBV相关PTLD，艾滋病相关淋巴瘤的铅化合物。 尽管在所有人口中都普遍存在，但EBV是淋巴瘤和免疫损害的人疾病（PTLD），各种B和T细胞淋巴瘤（L）和Hodgkin的淋巴瘤（HL）的重要原因。 EBV在口咽上皮细胞中复制，并在B淋巴细胞中建立潜伏期。 在B细胞中，EBV可以建立3种类型的延迟。 EBV潜伏期生病，表达6个EB核抗原（EBNA）和两种整合膜蛋白（LMP1和2），并引起淋巴细胞增殖，这与PTLD是无法区分的。 通常，潜伏期型LLL细胞被T淋巴细胞识别，并且随着免疫反应的发展而容易消除。 某些感染的B细胞持续存在于II型潜伏期中，其中仅表达EBNA1，LMP1和LMP2或在I型潜伏期I中，其中仅表达EBAN1。 EBNA1不受蛋白酶体途径的处理，从而避免CD8细胞毒性T细胞的识别。 EBNA1是EBV DNA持久性作为外染色体插发事件所需的唯一蛋白质。 EBNA1与Orip和染色体中的同源序列结合，使EBV DNA得以复制，维护，转录。 因此，抑制EBNA1功能可能是消除体内EBV感染细胞的有效方法。