Characterization of the Cyclic Di-GMP Signaling System of Vibrio cholerae

描述（由申请人提供）：霍乱弧菌是全球卫生大流行霍乱的病原体，它使用群体感应（QS）和环二gmp （c-diGMP）来调节生物膜的形成和毒力。QS是细菌分泌微小的化学信号来计算它们在种群中的数量并相应地控制群体行为的过程。c-diGMP是最近发现的在细菌中普遍存在的第二信使细胞内信号分子。我最近发现了霍乱弧菌中QS和c-diGMP之间的一种新的联系。为了回答关于c-diGMP的一些基本问题，并进一步了解它与QS的联系，本研究提出：使用遗传筛选鉴定将c-diGMP与基因表达改变偶联的转录成分；目标2。利用生物信息学和高通量化学筛选技术鉴定霍乱弧菌GGDEF/EAL蛋白的特异性配体；和Aim 3。利用x射线晶体学确定GGDEF和EAL蛋白的信号识别如何调节酶活性。由于QS和c-diGMP都能控制霍乱弧菌和许多其他细菌病原体的毒力，我希望这项工作可以为治疗细菌性疾病带来新的治疗方法。”细菌通过感知多种微小的化学信号来适应和应对环境。这些化学信号通常控制着细菌引起疾病的能力。我在霍乱弧菌的研究旨在揭示这些信号的本质，以及细菌如何对它们做出反应，以开发新的治疗方法来治疗细菌感染。相关性（见说明）：K22研究学者发展奖将允许我在我的新教师职位的头两年支持我的实验室成员（研究生，技术员和/或博士后）。这将使我能够开发研究项目，这将形成一个或多个R01赠款的基础。

DESCRIPTION (provided by applicant): Vibrio cholerae, the causative agent of the worldwide health pandemic cholera, uses both quorum sensing (QS) and cyclic di-GMP (c-diGMP) to regulate biofilm formation and virulence. QS is a process by which bacteria secrete small, chemical signals to count their numbers in a population and control group behavior accordingly. c-diGMP is a recently discovered second messenger intracellular signaling molecule ubiquitous in bacteria. I have recently discovered a novel connection between QS and c-diGMP in V. cholerae. To answer some of the fundamental question about c-diGMP, and further understand its connection to QS, this research proposes to: Aim 1. Identify the transcriptional components that couple c-diGMP to alterations in gene expression using genetic screens; Aim 2. Identify specific ligands of GGDEF/EAL proteins in V. cholerae using bioinformatics and a high-throughput chemical screen; and Aim 3. Utilize X-ray crystallography to determine how signal recognition by GGDEF and EAL proteins modulates enzymatic activity. As both QS and c-diGMP control virulence in V. cholerae and numerous other bacteria pathogens, it is my hope that this work could lead to novel therapeutic approaches for the treatment of bacterial disease. ' Bacteria sense multiple small chemical signals to adapt and respond to their environment. These chemical signals are often control the ability of bacteria to cause disease. My research in Vibrio cholerae seeks to unravel the nature of these signals, and how bacteria respond to them, to develop novel therapeutic approaches to treat bacterial infections. RELEVANCE (See instructions): The K22 Research Scholar Development Award will allow me to support members of my laboratory (graduate students, technician, and/or post-docs) during the first two years of my new faculty position. This will allow me to develop research projects that will form the basis of one or more R01 grants.