Probing the Function and Evolution of the Bacterial Envelope Architecture

探究细菌包膜结构的功能和进化

• 批准号: 7870528
• 负责人: Athanasios Typas
• 金额: $ 9万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7870528
• 关键词: Adverse effects; Affect; Amaze; Animal Model; Architecture; Area; Arts; Assimilations; Award; Bacteria; Bacterial Infections; Bioinformatics; Biological; Biological Assay; Biological Process; Biology; Biomass; Biometry; Cells; Chemicals; Collaborations; Communities; Complex; Computer Architectures; Country; Cytoplasm; Data; Data Set; Development; Development Plans; Dimensions; Dissection; Distant; Drug Delivery Systems; Drug resistance; Environment; Equipment; Escherichia coli; Evolution; Fatty Acids; Fellowship; Foundations; Generations; Genes; Genetic; Genetic Epistasis; Genome; Genomics; Goals; Grant; Growth; Hand; Host Defense; Investigation; Knock-out; Knowledge; Laboratories; Leadership; Letters; Libraries; Life Style; Link; Maps; Mentors; Methodology; Methods; Microbe; Modeling; Molds; Molecular; Monitor; Nature; Organism; Partner in relationship; Pathogenesis; Pathway interactions; Peptidoglycan; Pharmaceutical Preparations; Phase; Phospholipids; Phylogenetic Analysis; Planets; Play; Positioning Attribute; Process; Prokaryotic Cells; Proliferating; Proteins; Published Comment; Publishing; Quantitative Genetics; Relative (related person); Research; Research Personnel; Resolution; Resources; Robotics; Role; SECTM1 gene; Saccharomyces cerevisiae; Salmonella; Salmonella typhimurium; Schools; Scientist; Seminal; Signal Transduction; Source; Streptococcus pneumoniae; Stress; Systems Biology; Technology; Time; TimeLine; Training; Trees; Type III Secretion System Pathway; Work; base; career; career development; cell envelope; cell growth regulation; chemical genetics; combat; combinatorial; data integration; deletion library; environmental change; experience; extracellular; fitness; foodborne illness; functional genomics; gene function; genetic profiling; genome-wide; high throughput technology; improved; insight; knockout gene; meetings; membrane assembly; mutant; novel; pathogen; pressure; protein complex; public health relevance; research study; response; scale up; skills; stem; tool; uptake

DESCRIPTION (provided by applicant): Genomics-based resources for model organisms have recently fuelled the development of various functional genomics approaches that all aim to accelerate our ability to understand gene function and map cellular pathways/protein complexes. Some of the most powerful global approaches are based on scaling up long- standing concepts in biology, i.e. epistasis/genetic interactions - how the function of one gene depends on the function of a second gene, and chemical genetic interactions - how the function of one gene affects cellular responses to chemical stress, finding a quantitative readout for them and devising ways to globally assess the data and maximize the extracted information. UCSF has played a pivotal role in the above process, perfecting the genetic interaction technology for S. cerevisiae and adding a new dimension to the biology that can be extracted from these methods. The highly collaborative and interactive research spirit that characterizes the school, and its optimized pipeline of state-of-the-art robotic equipment and complementary facilities make UCSF a unique place for extending these technologies to other organisms. Since I arrived at UCSF on a prestigious EMBO fellowship, I have led an effort to develop such methodologies for prokaryotes and apply them to infer mechanistic insights on their biology. The technology we recently published for E. coli was featured in two comment articles, and our current work on generating a systematic chemical genetic profiling of the entire E. coli genome and a comprehensive genetic interaction map for its envelope compartment is almost completed and contains numerous insights on new biology. Here, I propose to develop and implement equivalent technology for the first time in a model pathogenic micoorganism, S. typhimurium. Having comparable data in both E. coli and S. typhimurium will allow me to perform a seminal comprehensive cross-species study in prokaryotes and monitor how simple and closely related unicellular organisms adjust their networks to adapt to different lifestyles and meet the needs of versatile environments. This effort will be extended as tools and data for key gram-positive organisms become available. Being trained as a biochemist and molecular microbiologist in my undergraduate and graduate studies, I have become confident in tackling hypothesis-driven questions on mechanism in a variety of fields. I also have acquired important skills in systems biology in the past two years, but to assume a leadership role and be able to drive this field forward, I need additional training in bioinformatics/biostatistics and pathogenesis. For this I have organized a rigorous career development plan that includes: a) a selection of targeted coursework, b) a team of world-leading scientists with cutting-edge expertise on all possible aspects of this project as my advisory board and c) two inspiring mentors who have been helping me all along in my systems biology endeavors; their experience and guidance will both facilitate the progress of the proposed work and help me improve my personal skills as a group leader. A plethora of mechanistic inferences stemming out of the proposed work will serve as a jumping-off point for my own lab. I envision my independent investigator career being in the interface of systems biology and hypothesis-driven mechanistic research, bridging the two to improve our knowledge on various key-biological aspects such as membrane assembly, regulation of cell growth and division, signal transduction, transcriptional cascades, drug assimilation/side- effects and combinatorial use, and evolutionary adaptation. PUBLIC HEALTH RELEVANCE: Bacteria are among the simplest and at the same time most diverse organisms in nature. Here, we propose to build the first comprehensive picture of the functional network organization of a compartment that constitutes the bacterium's interface to the environment. Our efforts will be concentrated on two closely related organisms, S. typhimurium, the number one cause of food-borne illnesses in western countries, and a harmless "domesticated" E. coli strain. Comparisons between the two organisms will illuminate important aspects of bacterial evolution and pathogenesis, and the information can be used to understand the mode of action of novel drugs and improve therapy for bacterial disease.

描述（由申请人提供）：基于基因组学的模式生物资源最近推动了各种功能基因组学方法的发展，所有这些方法都旨在提高我们理解基因功能和绘制细胞途径/蛋白质复合物图谱的能力。一些最强大的全球方法基于扩大生物学中长期存在的概念，即上位性/遗传相互作用——一个基因的功能如何依赖于另一个基因的功能，以及化学遗传相互作用——一个基因的功能如何依赖于另一个基因的功能。基因影响细胞对化学应激的反应，找到它们的定量读数，并设计全局评估数据和最大化提取信息的方法。加州大学旧金山分校在上述过程中发挥了关键作用，完善了酿酒酵母的遗传相互作用技术，并为从这些方法中提取的生物学添加了新的维度。学校的高度协作和互动研究精神，以及最先进的机器人设备和配套设施的优化管道，使加州大学旧金山分校成为将这些技术扩展到其他生物体的独特场所。自从我获得著名的 EMBO 奖学金来到加州大学旧金山分校以来，我一直致力于开发原核生物的此类方法，并将其应用于推断其生物学的机制见解。我们最近发表的大肠杆菌技术在两篇评论文章中得到了重点介绍，我们目前对整个大肠杆菌基因组进行系统化学遗传分析及其包膜区室的全面遗传相互作用图谱的工作已基本完成，并且包含大量对新生物学的见解。在这里，我建议首次在模型病原微生物——鼠伤寒沙门氏菌中开发和实施等效技术。拥有大肠杆菌和鼠伤寒沙门氏菌的可比较数据将使我能够在原核生物中进行开创性的全面跨物种研究，并监测简单且密切相关的单细胞生物如何调整其网络以适应不同的生活方式并满足多功能环境的需求。随着关键革兰氏阳性生物的工具和数据的出现，这项工作将得到扩展。在我的本科和研究生学习中，我接受了生物化学家和分子微生物学家的培训，我对解决各个领域的假设驱动的机制问题充满信心。在过去的两年里，我还获得了系统生物学的重要技能，但为了发挥领导作用并能够推动这一领域向前发展，我需要在生物信息学/生物统计学和发病机制方面接受额外的培训。为此，我组织了一个严格的职业发展计划，其中包括：a）选择有针对性的课程，b）由世界领先的科学家组成的团队，作为我的顾问委员会，他们在该项目的所有可能方面拥有尖端专业知识，c）两个鼓舞人心的导师，他们一直在我的系统生物学事业中帮助我；他们的经验和指导将促进拟议工作的进展，并帮助我提高作为小组领导者的个人技能。拟议工作中产生的大量机械推论将作为我自己实验室的起点。我设想我的独立研究者职业生涯是在系统生物学和假设驱动的机制研究的界面上，将两者联系起来，以提高我们对各种关键生物学方面的知识，例如膜组装、细胞生长和分裂的调节、信号转导、转录级联、药物同化/副作用和组合使用以及进化适应。 公共卫生相关性：细菌是自然界中最简单但同时也是最多样化的生物体之一。在这里，我们建议构建构成细菌与环境界面的隔室功能网络组织的第一个全面图景。我们的努力将集中在两种密切相关的生物体上：鼠伤寒沙门氏菌（西方国家食源性疾病的头号病因）和无害的“驯化”大肠杆菌菌株。两种生物体之间的比较将阐明细菌进化和发病机制的重要方面，这些信息可用于了解新药的作用方式并改进细菌性疾病的治疗。