Role of cyclo(Phe-Pro) in Vibrio cholerae virulence factor production

环(Phe-Pro)在霍乱弧菌毒力因子产生中的作用

• 批准号: 8423427
• 负责人: JAMES Edward BINA
• 金额: $ 19.39万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-15 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8423427
• 关键词: Role; cyclo; Phe; Pro; Vibrio

DESCRIPTION (provided by applicant): Vibrio cholerae is a facultative human pathogen that causes the severe diarrheal disease cholera. The ability of V. cholerae to cause disease is dependent upon the regulated expression of virulence factors. For example, the virulence genes encoding for production of cholera toxin and the toxin coregulated pilus appear to be induced early in infection and repressed late in infection before exiting the human gastrointestinal tract. Other genes that are induced late during infection are believed to be important for the establishment of the hyperinfective phenotype exhibited by human shed vibrios, and for survival in the aquatic ecosystem. The mechanisms that control gene expression in vivo are largely unknown. Quorum sensing has been proposed as one potential mechanism to govern late gene expression in vivo. However, the observation that many epidemic V. cholerae strains are quorum sensing insensitive suggests that other regulatory mechanisms must exist. Our laboratory has shown that diketopiperazines inhibit virulence factor production in V. cholerae. In this grant we will test the hypothesis that cyclo(Phe-Pro), a natural diketopiperazine produced by V. cholerae, functions as a signal to modulate virulence gene expression independent of the known quorum sensing systems. Two specific aims are proposed. In specific aim 1 we will characterize cyclo(Phe-Pro) and define genes that are involved in its synthesis . In specific aim 2 we will define the mechanism by which cyclo(Phe-Pro) regulates virulence factor production. These studies will shed light on a novel regulatory system that controls virulence factor production and may facilitate the future development of novel therapeutic approaches for treatment of cholera.

描述（由申请方提供）：霍乱弧菌是一种兼性人类病原体，可引起严重的霍乱弧菌病。霍乱弧菌引起疾病的能力取决于毒力因子的调节表达。例如，编码产生霍乱毒素和毒素共调节菌毛的毒力基因似乎在感染早期被诱导，并在感染后期在离开人胃肠道之前被抑制。在感染后期被诱导的其他基因被认为对于人类脱落弧菌所表现出的高感染表型的建立以及对于在水生生态系统中的存活是重要的。控制体内基因表达的机制在很大程度上是未知的。群体感应被认为是体内控制晚期基因表达的一种潜在机制。然而，许多流行性霍乱弧菌菌株对群体感应不敏感的观察结果表明，必须存在其他调节机制。我们的实验室已经表明，二酮哌嗪抑制霍乱弧菌中毒力因子的产生。在这项研究中，我们将测试的假设，环（Phe-Pro），一个天然的二酮哌嗪产生的霍乱弧菌，作为一个信号，调节毒力基因的表达独立于已知的群体感应系统。提出了两个具体目标。在具体目标1中，我们将表征环状（Phe-Pro）并定义参与其合成的基因。在具体目标2中，我们将定义cyclo（Phe-Pro）调节毒力因子产生的机制。这些研究将揭示一种新的调控系统，控制毒力因子的生产，并可能促进未来开发新的治疗方法治疗霍乱。