Role of Calcium Signaling in HSV-2 Invasion

钙信号传导在 HSV-2 侵袭中的作用

• 批准号: 6923525
• 负责人: Betsy C. Herold
• 金额: $ 36.4万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-15 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6923525
• 关键词: HIV envelope protein gp120; biological signal transduction; calcium flux; cellular polarity; clinical research; glycoproteins; herpes simplex virus 2; human tissue; membrane transport proteins; phosphorylation; phosphotransferases; tissue /cell culture; virus cytopathogenic effect; virus infection mechanism

DESCRIPTION (provided by applicant): Topical microbicides that block transmission of herpes simplex virus (HSV) and other sexually transmitted pathogens are urgently needed. The observation that heparan sulfate proteoglycans serve as attachment receptors propelled the development of sulfonated polymers, which are now in clinical trial, as candidate microbicides. Identification of new agents that target steps post-binding requires elucidation, at a molecular level, of the signaling pathways required for fusion of the viral envelope with the cell plasma membrane and nuclear transport of viral capsids. Preliminary studies indicate that viral invasion requires activation of calcium (Ca2+) signaling and tyrosine phosphorylation of focal adhesion kinase (FAK) and other cellular proteins. Activation of Ca2+ and phosphorylation signaling pathways are common mechanisms associated with invasion by other microbes, most notably HIV. The studies proposed in this application build on these observations. Focusing on HSV serotype 2 (HSV-2), the predominant cause of genital herpes, these studies will examine the cellular signaling pathways required for viral invasion and the role viral envelope glycoproteins play in this process. Most studies of viral entry have been conducted using permanent non-polarized epithelial cell lines. However, the polarity of epithelial cells is fundamental to their structure and function and influences susceptibility to infection. Preliminary work indicates that HSV- 2 infection of polarized epithelial cells is more efficient following apical compared to basolateral exposure. Therefore, the mechanism of viral invasion in polarized cell culture systems will also be explored. Observations in polarized cells will more accurately reflect the conditions in vivo. Results of these studies will enhance understanding of the molecular biology of HSV invasion and should facilitate the rational design of new topical antimicrobials to prevent HSV transmission and acquisition.

描述（由申请人提供）：迫切需要迫切需要刺激单纯疱疹病毒（HSV）和其他性传播病原体的局部菌皮。硫酸乙酰肝素蛋白聚糖作为固定受体的观察结果推动了磺酸聚合物的发展，这些聚合物现在正在临床试验中，作为候选菌心。 鉴定靶向后固定后的新药物需要在分子水平上阐明病毒包膜与细胞质膜和病毒capsids的核转运所需的信号传导途径。 初步研究表明，病毒侵袭需要激活局灶性粘附激酶（FAK）和其他细胞蛋白的钙（CA2+）信号传导和酪氨酸磷酸化。 Ca2+和磷酸化信号通路的激活是与其他微生物侵袭有关的常见机制，最著名的是HIV。 本应用程序中提出的研究基于这些观察结果。 这些研究着重于HSV血清型2（HSV-2），这是生殖器疱疹的主要原因，这些研究将检查病毒侵袭所需的细胞信号传导途径，并在此过程中扮演病毒式糖糖蛋白的作用。 大多数病毒进入的研究都是使用永久性非极化上皮细胞系进行的。 但是，上皮细胞的极性是其结构和功能的基础，并影响了感染的易感性。 初步工作表明，与基底外侧暴露相比，偏振上皮细胞的HSV-2感染更有效。 因此，还将探索极化细胞培养系统中病毒侵袭的机制。 极化细胞中的观测将更准确地反映体内条件。 这些研究的结果将增强对HSV侵袭的分子生物学的理解，并应促进新的局部抗菌剂的合理设计，以防止HSV传播和获取。