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

基本信息

批准号：
8640069
负责人：
JAMES Edward BINA
金额：
$ 38.78万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
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/8640069
关键词：
Affect Anabolism Animals Attenuated Bacteria Chemicals Cholera Cholera Toxin Conditioned Culture Media Data Development Diarrhea Dipeptides Disease Ecosystem Environment Epidemic Exhibits Future Gastrointestinal tract structure Gene Expression Gene Expression Regulation Genes Genetic Transcription Goals Gram-Negative Bacteria Grant Growth Human Infant Infection Ingestion Laboratories Light Mediating Mediator of activation protein Modeling Mus Mutation Nature Phenotype Pilum Play Production Proliferating Publishing Regulation Regulon Reporting Research Role Signal Transduction Signal Transduction Pathway Small Intestines System Testing Therapeutic Toxin Uncertainty Vibrio Vibrio cholerae Virulence Virulence Factors Work diketopiperazine gene function in vivo novel novel therapeutic intervention overexpression pathogen peptide synthase plant fungi public health relevance quorum sensing success vibriobactin

项目摘要

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. PUBLIC HEALTH RELEVANCE: The proposed research will characterize a potential chemical signal that is involved in the regulated expression of virulence factor production in Vibrio cholerae. Characterization of this chemical signal will advance our understanding of how Vibrio cholerae causes disease and may elucidate potential therapeutic approaches to control the spread of cholera.

描述（由申请人提供）：霍乱弧菌是一种兼性人类病原体，可引起严重腹泻病霍乱。霍乱弧菌引起疾病的能力取决于毒力因子表达的调节。例如，编码产生霍乱毒素和共同调节菌毛的毒力基因似乎在感染早期被诱导，并在感染晚期在离开人胃肠道之前被抑制。人们认为，在感染后期诱导的其他基因对于人类棚弧菌表现出的过度感染表型的建立以及在水生生态系统中的生存很重要。体内控制基因表达的机制很大程度上是未知的。群体感应已被提议作为控制体内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表明，必须存在其他调节机制。我们的实验室已证明二酮哌嗪类药物可抑制霍乱弧菌毒力因子的产生。在这笔资助中，我们将测试以下假设：环（Phe-Pro）是由霍乱弧菌产生的天然二酮哌嗪，其作为独立于已知群体感应系统调节毒力基因表达的信号发挥作用。提出了两个具体目标。在具体目标 1 中，我们将表征 cyclo(Phe-Pro) 并定义参与其合成的基因。在具体目标 2 中，我们将定义环（Phe-Pro）调节毒力因子产生的机制。这些研究将揭示一种控制毒力因子产生的新型调节系统，并可能促进未来治疗霍乱的新型治疗方法的发展。公共健康相关性：拟议的研究将描述霍乱弧菌毒力因子产生的调节表达所涉及的潜在化学信号。这种化学信号的表征将增进我们对霍乱弧菌如何引起疾病的理解，并可能阐明控制霍乱传播的潜在治疗方法。