Local and global regulation of bacterial growth

为了影响人类健康，细菌必须通过连续几轮的生长和分裂进行繁殖。 此外，细菌细胞必须使它们的生长适应不断变化的环境条件，包括 营养供应或抗生素的存在，以确保生存。在我们提议的工作中，我们重点关注两个 与细菌生长和适应有关的问题。首先，我们问细菌细胞是如何局部调节的 细胞分裂过程中的生长(胞质分裂)？为了解决这个问题，我们将在最近的工作基础上再接再厉 证明保守的聚合GTPase FtsZ是细胞壁合成的动态调节因子 细胞分裂过程中的重塑。这一想法代表了将FtsZ定义为主动监管机构的范式转变， 而不是被动的支架，用于细胞壁的新陈代谢。我们将利用我们在细菌遗传学方面的专业知识， 成像、生物化学和体外重建以绘制两个信号中的角色和机制 从FtsZ到细胞壁代谢的途径，我们在我们的模式生物新月弯杆菌中发现了。 鉴于迫切需要新的抗生素，以及细胞壁作为抗菌靶标的有效性已得到证实， 完全了解细胞壁代谢的机制和调节是一个关键的目标。在我们的 第二个问题，我们问细菌如何适应营养供应和其他压力的变化？我们 最近描述了一种名为CDNL的保守转录调节因子在调节新陈代谢中的作用， 特别是在弧菌中上调生物合成途径。此外，我们还观察到CDNL是 在营养限制期间以依赖于信号警报ppGpp的方式从细胞中清除， 这表明了一种机制，当营养稀缺时，细胞可以通过这种机制下调增殖过程。 我们将使用遗传、基因组和生化方法的组合来确定 CDNL失活和ppGpp重新编程转录以确保细菌在营养期间存活 限制和其他压力。因为CDNL和ppGpp都参与了对多种压力的适应 不同的细菌，这项工作将有助于我们理解应激和抗生素耐药机制 重要的细菌病原体。 项目总结是对拟议工作的简明和准确的描述，应该能够站得住脚 它本身(独立于应用程序)。这一部分应该对在 相同或相关的领域，有科学素养的读者可以理解。避免对过去的两种描述 成就和第一人称的使用。请言简意赅。 格式： 本部分限制为30行文本，并且必须遵循所需的字体和页边距规范。一个 超过此长度的摘要将在提交时被机构标记为错误。您将需要 在申请被接受之前采取纠正措施。 将此信息附加为PDF文件。请参阅“设置附件格式”页面。 内容： 说明应用程序的广泛、长期目标和具体目标，并参考健康 项目的关联性(即与机构使命的关联性)。描述研究设计和 实现所述目标的方法。确保项目摘要反映了 建议的项目，以便对应用程序进行适当的分类。 不要在项目摘要中包含专有、机密信息或商业秘密。如果应用程序是 在资助下，项目摘要将被输入NIH数据库，并在NIH Research上提供 投资组合在线报告工具(Report)，并将成为公开信息。 请注意，“项目摘要/摘要”附件与“研究策略”附件不同。

To impact human health, bacteria must reproduce through successive rounds of growth and division. Moreover, bacterial cells must adapt their growth to changing environmental conditions, including changes in nutrient availability or the presence of antibiotics, to ensure survival. In our proposed work, we focus on two questions relevant to bacterial growth and adaptation. In the first, we ask how do bacterial cells locally regulate growth during cell division (cytokinesis)? To address this question, we will build on our recent work demonstrating that the conserved polymerizing GTPase FtsZ is a dynamic regulator of cell wall synthesis and remodeling during cell division. This idea represents a paradigm shift in defining FtsZ as an active regulator, rather than passive scaffold, for cell wall metabolism. We will leverage our expertise in bacterial genetics, imaging, biochemistry, and in vitro reconstitution to map the players and mechanisms in two signaling pathways from FtsZ to cell wall metabolism we identified in our model organism, Caulobacter crescentus. Given the urgent need for new antibiotics and proven efficacy of the cell wall as an antibacterial target, a complete understanding of the mechanisms and regulation of cell wall metabolism is a critical goal. In our second question, we ask how do bacteria adapt to changing nutrient availability and other stresses? We recently described the role of a conserved transcriptional regulator called CdnL in regulating metabolism, specifically in upregulating biosynthetic pathways, in Caulobacter. In addition, we have observed that CdnL is cleared from the cell during nutrient limitation in a manner dependent on the signaling alarmone ppGpp, suggesting a mechanism by which cells may downregulate proliferative processes when nutrients are scarce. We will use a combination of genetic, genomic, and biochemical approaches to determine the contributions of CdnL inactivation and ppGpp to reprogramming transcription to ensure bacterial survival during nutrient limitation and other stresses. As both CdnL and ppGpp are implicated in adaptation to a variety of stresses in diverse bacteria, this work will inform our understanding stress and antibiotic resistance mechanisms in important bacterial pathogens. The project summary is a succinct and accurate description of the proposed work and should be able to stand on its own (separate from the application). This section should be informative to other persons working in the same or related fields and understandable to a scientifically literate reader. Avoid both descriptions of past accomplishments and the use of the first person. Please be concise. Format: This section is limited to 30 lines of text, and must follow the required font and margin specifications. A summary which exceeds this length will be flagged as an error by the Agency upon submission. You will need to take corrective action before the application can be accepted. Attach this information as a PDF file. See the Format Attachments page. Content: State the application's broad, long-term objectives and specific aims, making reference to the health relatedness of the project (i.e., relevance to the mission of the agency). Describe the research design and methods for achieving the stated goals. Be sure that the project summary reflects the key focus of the proposed project so that the application can be appropriately categorized. Do not include proprietary, confidential information or trade secrets in the project summary. If the application is funded, the project summary will be entered into an NIH database and made available on the NIH Research Portfolio Online Reporting Tool (RePORT) and will become public information. Note that the "Project Summary/Abstract" attachment is not same as the "Research Strategy" attachment.