Physiological and Developmental Role of Bacterial Ser/Thr Kinases

项目摘要 细菌利用信号系统来感知和响应环境。这使他们能够调整自己的 细胞生理学和集体行为对环境线索的反应。这些系统的一个子集 是汉克斯型丝氨酸/苏氨酸激酶和磷酸酶。这些信号系统已被证明， 对细菌生理学，包括细胞生长和分裂，抗生素， 耐受性和抗性、孢子形成和萌发、毒力和生物膜形成。为了实现这一点， 这些系统可以通过酶的直接翻译后修饰来调节细胞功能，或者 通过增加一个额外的调节层来控制转录， 途径。因此，对汉克斯型Ser/Thr信号系统的活性仍然知之甚少， 特别是在单细胞水平上，已知这些系统调节稀有细胞的出现 具有极端的表型，例如增加的抗生素抗性和细菌毒力。的长期目标 我的实验室正在探索这些信号系统如何调节群体和单细胞水平的表型 从而了解它们对人类健康和疾病的贡献。为了做到这一点，我们将1）执行一个 保守的细菌汉克斯型丝氨酸/苏氨酸激酶-磷酸酶系统的机制和定量研究， 专注于了解它们的调控结构如何使细菌中的稀有细胞产生， 具有极端表型的群体，2）确定这些信号系统在发育中的作用 转化，如感受态、生物膜形成和孢子形成。首先，我们将重点介绍这些系统， 模式生物枯草芽孢杆菌，其长期目标是揭示可以被 推广到其他遗传上不太容易处理的和临床上重要的细菌。

Project Summary Bacteria employ signaling systems to sense and respond to their environment. This allows them to adjust their cellular physiology and collective behavior in response to environmental cues. One subset of these systems are the Hanks-type serine/threonine kinases and phosphatases. These signaling systems have been shown to be critical, and even often essential, for bacterial physiology, including cell growth and division, antibiotic tolerance and resistance, sporulation and germination, virulence, and biofilm formation. To accomplish this, these systems can regulate cellular function through direct post-translational modification of enzymes, or control transcription by adding an additional layer of regulation to the activity of transcription factors from other pathways. As a result, the activity of Hanks-type Ser/Thr signaling systems remains poorly understood, particularly at the single-cell level, where these systems are known to regulate the appearance of rare cells with extreme phenotypes such as increased antibiotic resistance and bacterial virulence. The long-term goal of my laboratory is to explore how these signaling systems regulate population and single-cell-level phenotypes and thereby to understand their contribution to human health and disease. To do so, we will 1) perform a mechanistic and quantitative study of conserved bacterial Hanks-type Ser/Thr kinase-phosphatase systems, focused on understanding how their regulatory architecture enables the generation of rare cells in bacterial populations with extreme phenotypes, 2) determine the role of these signaling systems in developmental transitions such as competence, biofilm formation, and sporulation. Initially we will focus on these systems in the model organism Bacillus subtilis, with the long-term goal to uncover the conserved features that can be generalized to other, less genetically tractable, and clinically important bacteria.