Activation and Inhibition of Apoptotic Pathways by SV5

SV5 激活和抑制细胞凋亡途径

• 批准号: 7091820
• 负责人: Biao He
• 金额: $ 2.77万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-15 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7091820
• 关键词: Activation; Inhibition; Apoptotic; Pathways; SV5

EXCEED THE SPACE PROVIDED. Apoptosis plays important roles in pathogenesis of paramyxoviruses which includes many important pathogens. Mechanisms of activation and inhibition of apoptotic pathways by paramyxoviruses are not well understood. Tumor necrosis factor alpha (TNF) can be induced by paramyxovirus infection and can cause apoptosis of infected cells. Simian virus 5 (SV5), a paramyxovirus, does not cause apoptosis. However, deletion of the 44- amino-acid-residue small hydrophobic (SH) gene from SV5 resulted in a mutant virus that induced apoptosis and increased expression of TNF. It is hypothesized that the SH protein blocks apoptotic pathways activated by TNF and the SH protein may define a new class of anti-apoptosis proteins. Long term goals of this work are to understand how paramyxoviruses interact with host cell apoptotic pathways. The proposal focuses on following aims: (1) investigate mechanism of inhibition of TNF signaling pathways by the SH protein. It is shown in the preliminary studies that the SH protein is sufficient to inhibit TNF signaling. Key residues of SH that are important for its inhibitory effect and host cells with which SH interacts will be identified; (2) investigate mechanism of increased expression of TNF in the mutant virus infected cells. Expression of TNF in virus infected cells will be examined at transcriptional and translational levels. SV5 protein responsible for activating expression will be identified; (3) study anti-apoptosis functions of SH proteins encoded by other paramyxoviruses. SV5 containing SH genes from other paramyxoviruses in place of the SH gene of SV5 will be generated. Growth characteristics of the hybrid SV5 viruses will be examined and their abilities to induce apoptosis will be analyzed; and (4) investigate inhibition of apoptotic pathways by the hemagglutinin-neuraminidase (HN) protein of SV5. Like SH, HN, a type II membrane protein, has a small cytoplasmic tail of 16 amino acid residues. A recombinant SV5 with a deletion of the tail of HN induced apoptosis in HeLa T4 cells. The involvement of the HN protein in inhibiting apoptosis will be studied. PERFORMANCE SITE ========================================Section End===========================================

超出所提供的空间。细胞凋亡在副粘病毒的发病机制中起着重要的作用，副粘病毒包括许多重要的病原体。副粘病毒激活和抑制细胞凋亡途径的机制尚不清楚。肿瘤坏死因子α (TNF)可被副粘病毒感染诱导，并可引起感染细胞凋亡。猿猴病毒5 （SV5）是一种副粘病毒，不会引起细胞凋亡。然而，从SV5中删除44-氨基酸残基小疏水（SH）基因导致突变病毒诱导细胞凋亡和TNF表达增加。据推测，SH蛋白阻断TNF激活的凋亡通路，并可能定义一类新的抗凋亡蛋白。这项工作的长期目标是了解副粘病毒如何与宿主细胞凋亡途径相互作用。本研究的主要目的是：(1)研究SH蛋白抑制TNF信号通路的机制。初步研究表明，SH蛋白足以抑制TNF信号。SH的关键残基对其抑制作用和与SH相互作用的宿主细胞很重要；(2)探讨突变病毒感染细胞中TNF表达升高的机制。TNF在病毒感染细胞中的表达将在转录和翻译水平上进行检测。鉴定激活表达的SV5蛋白；(3)研究其他副粘病毒编码的SH蛋白的抗凋亡功能。将产生含有其他副粘病毒SH基因的SV5，取代SV5的SH基因。研究杂交SV5病毒的生长特性，分析其诱导细胞凋亡的能力；(4)研究SV5的血凝素-神经氨酸酶（HN）蛋白对凋亡通路的抑制作用。与SH一样，II型膜蛋白HN也有一个由16个氨基酸残基组成的小细胞质尾部。缺失HN尾部的重组SV5诱导HeLa T4细胞凋亡。我们将进一步研究HN蛋白在抑制细胞凋亡中的作用。网站性能 ======================================== 节结束 ===========================================