Local and global regulation of bacterial growth

细菌生长的局部和全局调节

基本信息

批准号：
10793783
负责人：
Erin D Goley
金额：
$ 7.65万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10793783
关键词：
Address Anti-Bacterial Agents Antibiotic Resistance Antibiotics Bacteria Biochemical Biochemistry Categories Caulobacter Caulobacter crescentus Cell Wall Cell division Cells Confidential Information Cytokinesis Databases Development Ensure Funding Genetic Genetic Transcription Genomics Goals Growth Guanosine Triphosphate Phosphohydrolases Health Human Image In Vitro Length Maps Metabolism Mission Nutrient Nutrient availability Pathway interactions Persons Process Reader Regulation Reporting Reproduction Research Research Design Research Methodology Role Signal Pathway Signal Transduction Specific qualifier value Starvation Stress Text United States National Institutes of Health Work bacterial genetics environmental change model organism novel pathogenic bacteria reconstitution resistance mechanism scaffold scientific literacy tool transcriptional reprogramming

项目摘要

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.

为了影响人类健康，细菌必须通过连续几轮的生长和分裂来繁殖。此外，细菌细胞必须使其生长适应不断变化的环境条件，包括环境条件的变化营养物质的可用性或抗生素的存在，以确保生存。在我们提出的工作中，我们重点关注两个与细菌生长和适应相关的问题。首先，我们问细菌细胞如何局部调节细胞分裂过程中的生长（细胞分裂）？为了解决这个问题，我们将在最近的工作基础上证明保守的聚合 GTPase FtsZ 是细胞壁合成的动态调节剂细胞分裂过程中的重塑。这个想法代表了将 FtsZ 定义为主动监管机构的范式转变，而不是被动支架，用于细胞壁代谢。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，以绘制两种信号传导的参与者和机制我们在模型生物新月柄杆菌中发现了从 FtsZ 到细胞壁代谢的途径。鉴于对新抗生素的迫切需求以及细胞壁作为抗菌靶标的功效已得到证实，完整了解细胞壁代谢的机制和调节是一个关键目标。在我们的第二个问题，我们问细菌如何适应不断变化的营养供应和其他压力？我们最近描述了一种名为 CdnL 的保守转录调节因子在调节代谢中的作用，特别是在柄杆菌中上调生物合成途径。此外，我们观察到 CdnL 在营养限制期间以依赖于信号报警素 ppGpp 的方式从细胞中清除，提出了一种机制，当营养物质稀缺时，细胞可以下调增殖过程。我们将结合使用遗传、基因组和生化方法来确定 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。由于 CdnL 和 ppGpp 都与适应各种应激有关不同的细菌，这项工作将有助于我们了解细菌的压力和抗生素耐药性机制重要的细菌病原体。项目摘要是对拟议工作的简洁、准确的描述，并且应该能够经受住考验单独（与应用程序分开）。本节应该为在该领域工作的其他人员提供信息相同或相关的领域，并且对于具有科学素养的读者来说是可以理解的。避免对过去的描述成就和第一人称的使用。请简明扼要。格式：此部分的文本长度不得超过 30 行，并且必须遵循所需的字体和边距规范。一个超过此长度的摘要将在提交时被 FDA 标记为错误。你将需要在接受申请之前采取纠正措施。将此信息附加为 PDF 文件。请参阅格式附件页面。内容：陈述应用程序的广泛、长期目标和具体目标，并参考健康项目的相关性（即与机构使命的相关性）。描述研究设计和实现既定目标的方法。确保项目摘要反映了项目的重点提议的项目，以便可以对应用程序进行适当的分类。请勿在项目摘要中包含专有、机密信息或商业秘密。如果应用程序是获得资助后，项目摘要将被输入 NIH 数据库并在 NIH 研究中心提供投资组合在线报告工具（RePORT）并将成为公共信息。请注意，“项目摘要/摘要”附件与“研究策略”附件不同。