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(申请人提供)：以基因组学为基础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，这些方法都旨在加快我们理解基因功能和绘制细胞途径/蛋白质复合体的能力。一些最强大的全球方法是基于放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取决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影响细胞对化学胁迫的反应，为它们找到一个定量读数，并设计出全局评估数据和最大化提取信息的方法。UCSF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增加了新的维度。这所学校的特点是高度协作和互动的研究精神，其最先进的机器人设备和补充设施的优化管道使加州大学旧金山分校成为将这些技术推广到其他生物体的独特场所。自从我以一项享有盛誉的EMBO奖学金来到加州大学旧金山分校以来，我一直在领导一项努力，为原核生物开发这种方法，并将其应用于推断对其生物学的机械性见解。我们最近为大肠杆菌发表的技术出现在两篇评论文章中，我们目前的工作是为整个大肠杆菌基因组生成系统的化学遗传图谱，并为其包膜隔间生成一个全面的遗传相互作用图，其中包含了对新生物学的许多见解。在这里，我建议第一次在模型致病微生物鼠伤寒沙门氏菌中开发和实施相同的技术。拥有大肠杆菌和鼠伤寒沙门氏菌的可比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，并监测简单而密切相关的单细胞生物如何调整它们的网络，以适应不同的生活方式和满足多样化环境的需求。随着关键革兰氏阳性细菌的工具和数据可用，这项工作将得到扩展。在本科和研究生学习期间，我接受了生物化学家和分子微生物学家的培训，我已经变得有信心在不同领域解决假说驱动的机制问题。在过去的两年里，我还获得了系统生物学方面的重要技能，但为了承担领导角色并能够推动这一领域的发展，我需要在生物信息学/生物统计学和发病机制方面进行额外的培训。为此，我组织了一份严格的职业发展计划，其中包括：a)选择有针对性的课程工作，b)作为我的顾问委员会，拥有这个项目所有可能方面的尖端专业知识的世界领先的科学家团队，以及c)两位鼓舞人心的导师，他们一直在我的系统生物学努力中帮助我；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负责人的个人技能。从拟议的工作中产生的过多的机械论推论将作为我自己的实验室的起点。我设想我的独立研究人员的职业生涯是在系统生物学和假说驱动的机械论研究的交界处，将两者联系起来，以提高我们在各种关键生物学方面的知识，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。 与公共健康相关：细菌是自然界中最简单、同时也是最多样化的生物之一。在这里，我们建议建立构成细菌与环境的接口的隔室的功能网络组织的第一张全面图。我们的努力将集中在两种密切相关的生物上，一种是鼠伤寒沙门氏菌，它是西方国家食源性疾病的头号原因，另一种是一种无害的“驯化”的大肠杆菌菌株。对这两种生物的比较将阐明细菌进化和发病机制的重要方面，这些信息可以用来了解新药的作用模式和改进细菌疾病的治疗。