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：
8186812
负责人：
JAMES Edward BINA
金额：
$ 10.94万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
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 2011-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8186812
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 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）：Vibrio Cholerae是一种兼职人类病原体，会导致严重的腹泻病霍乱。 V.霍乱引起疾病的能力取决于毒力因子的调节表达。例如，编码用于产生霍乱毒素和毒素核心pilus的毒力基因似乎是在感染的早期引起的，并在退出人类胃肠道的后期被抑制。人们认为，在感染期间诱发的其他基因对于建立人类棚颤音表现出的过度感染表型以及在水生生态系统中的生存至关重要。在体内控制基因表达的机制在很大程度上是未知的。已经提出了法定人数传感作为控制体内晚期基因表达的一种潜在机制。然而，观察到许多流行病霍乱菌株是法定人数不敏感的，这表明必须存在其他调节机制。我们的实验室表明，二酮替嗪会抑制霍乱弧菌中的毒力因子的产生。在这笔赠款中，我们将检验以下假设：Cyclo（Phe-Pro）是霍乱弧菌生产的一种天然二甲苯嗪，它是调节与已知Quorum感应系统无关的毒力基因表达的信号。提出了两个具体目标。在特定的目标1中，我们将表征Cyclo（PHE-PRO）并定义与其合成有关的基因。在特定的目标2中，我们将定义Cyclo（PHE-Pro）调节毒力因子产生的机制。这些研究将阐明一种新的调节系统，该系统控制毒力因子的产生，并可能促进新型治疗方法的未来发展。公共卫生相关性：拟议的研究将表征与弧形霍乱中毒力因子产生的调节表达相关的潜在化学信号。该化学信号的表征将促进我们对颤音霍乱如何引起疾病的理解，并可能阐明潜在的治疗方法来控制霍乱的传播。