The Effect of Multicellularity on Bacterial Interactions and Diversity

多细胞性对细菌相互作用和多样性的影响

基本信息

批准号：
9509481
负责人：
Nicholas Anthony Lyons
金额：
$ 8.86万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9509481
关键词：
Actinobacteria class Affect Altruism Amino Acid Substitution Amino Acids Antibiotic Resistance Antibiotics Award Bacillus (bacterium)Bacillus subtilis Bacteria Bacterial Physiology Behavior Bioinformatics Biological Biological Assay Biology Catalogs Cells Complement Complex Cooperative Behavior DNA Sequencing Facility Data Data Set Development Discrimination Distant Drug resistance Evolution Exhibits Foundations Future Gene Expression Genes Genetic Transcription Genomics Goals Habitats Health Human Infection Knowledge Learning Life Style Light Mediating Mentors Mentorship Microbial Biofilms Microbiology Modeling Mutation Organism Output Pharmaceutical Preparations Phase Phenotype Population Postdoctoral Fellow Prevention Production Recording of previous events Research Research Personnel Resources Role Route Scientist Social Environment Solid Source Streptomyces Stress Structure System Technical Expertise Techniques Testing Training Variant Work antimicrobial bioinformatics resource career career development clinically relevant comparative genomics defense response experience experimental study fascinate fighting genome sequencing interest medical schools microbial mutant negative affect novel pressure prevent skills success trait transcriptome sequencing transcriptomics virtual whole genome

项目摘要

ABSTRACT Bacterial lifestyles can be extremely complex, manifested most strikingly in the formation of highly cooperative multicellular structures like biofilms. Beyond the inherent basic biological interest, these complex traits have significant impacts on how bacteria relate to human health both as a defense response leading to increased drug resistance and as a source of clinically-‐‑relevant antibiotics, which are often only produced in certain social contexts. In my post-‐‑doctoral work I have used the model bacterium Bacillus subtilis to study how multicellular behaviors affect the way bacteria interact with each other. I found that B. subtilis can judge whether or not neighboring cells are close relatives, a phenomenon called kin discrimination. They do this using the extensive and diverse complement of antimicrobial molecules that each strain produces. This kin discrimination behavior creates an evolutionary pressure to diversify, resulting in so much intraspecies variation that even very closely related strains cannot coexist in their natural habitat. The first aim of this proposal will focus on the consequences of kin discrimination, specifically whether a population can better resist invasion by non-‐‑kin cells than kin. This will inform our understanding of natural microbial populations living in and around us, and how they respond to outside influences. I will also learn important technical skills involved in experimental evolution, including genome sequencing, comparative genomics, and the bioinformatic and programming skills inherent to working with large genomic datasets. The second aim seeks to gain a better understanding of the diversity lurking within the B. subtilis species by examining three routes of evolutionary change: amino acid substitutions, gain/loss of entire genes, and changes in gene transcription. By looking across multiple strains in multiple multicellular contexts, I will be able to see which of these changes is most common in early strain divergence and which genes are under the most pressure to change. This will generate a catalog of evolutionary information that will be useful for many years and open many avenues of research for my own independent lab. The techniques involved, such as RNA sequencing and bioinformatic analyses, will be invaluable additions to my skillset. The third aim of this application will examine the generality of my findings in other bacteria. Given that B. subtilis use antibiotic molecules to recognize each other, I will look in the phylum of bacteria that produces the majority of approved antibiotics: Actinobacteria. Examining intraspecies interactions can help shed light on the evolution of antibiotic production and how best to mine for clinically relevant molecules. I will investigate the ability of the Actinobacteria Streptomyces to discriminate kin from non-‐‑kin, and whether this is mediated through antibiotic diversity. This project will be my introduction to Actinobacteria, with the long-‐‑term goal of studying other aspects of their fascinating multicellular lifecycle. The training I will continue to receive under Dr. Roberto Kolter at Harvard Medical School will give me a great foundation of microbiology experience on which to build my career. HMS provides a number of advantages that will facilitate my advancement, including core sequencing facilities, bioinformatic resources, and courses dedicated to career development. Additionally, I will receive specialized training from experts in the fields of microbial genomics and Actinobacteria biology to accomplish the goals of this proposal and broaden my development as a scientist. The knowledge and techniques I will acquire under this award will be instrumental in obtaining my career goals and becoming an effective independent investigator.

抽象的细菌的生活方式可能极其复杂，最显着的表现是形成高度除了固有的基本生物学意义之外，这些复杂的多细胞结构。性状对细菌与人类健康的关系有重大影响，既可以作为一种防御反应，也可以导致增加耐药性并作为临床相关抗生素的来源，这些抗生素通常仅在在我的博士后工作中，我使用了模型细菌枯草芽孢杆菌来研究如何做到这一点。多细胞行为影响细菌相互作用的方式，我发现枯草芽孢杆菌可以判断。邻近细胞是否是近亲，这种现象称为亲属歧视。利用每种菌株产生的广泛且多样的抗菌分子。歧视行为产生了多样化的进化压力，导致了如此多的种内现象即使是非常密切相关的菌株也无法在其自然栖息地共存。该提案的第一个目标将集中于亲属歧视的后果，特别是是否存在亲属歧视。与亲属相比，人类群体能够更好地抵抗非亲属细胞的入侵。这将有助于我们对自然的理解。我还将了解生活在我们体内和周围的微生物种群，以及它们如何应对外界影响。实验进化中涉及的重要技术技能，包括基因组测序、比较基因组学，以及处理大型基因组数据集所固有的生物信息学和编程技能。第二个目标旨在通过以下方式更好地了解潜伏在枯草芽孢杆菌物种内的多样性：检查进化变化的三种途径：氨基酸取代、整个基因的获得/丢失，以及通过观察多种多细胞环境中的多种菌株，我将了解基因转录的变化。能够看到哪些变化在早期菌株分化中最常见以及哪些基因受到影响最大的改变压力。这将生成一个对许多人有用的进化信息目录。多年来，为我自己的独立实验室开辟了许多研究途径。所涉及的技术，例如 RNA。测序和生物信息学分析将是对我技能的宝贵补充。本申请的第三个目标是检验我的发现在其他细菌中的普遍性。枯草芽孢杆菌使用抗生素分子来识别彼此，我将在产生抗生素分子的细菌门中寻找大多数已批准的抗生素：检查种内相互作用有助于揭示放线菌的情况。我将研究抗生素生产的演变以及如何最好地挖掘临床相关分子。放线菌链霉菌区分亲缘关系和非亲缘关系的能力，以及这是否是介导的通过抗生素多样性。这个项目将是我对放线菌的介绍，其长期目标是研究它们令人着迷的多细胞生命周期的其他方面。我将继续在哈佛医学院 Roberto Kolter 博士的指导下接受培训，这将为我提供良好的培训 HMS 为我的职业生涯提供了许多优势。这将促进我的进步，包括核心测序设施、生物信息资源和课程致力于职业发展。此外，我还将接受以下领域专家的专门培训微生物基因组学和放线菌生物学来实现本提案的目标并扩大我的研究范围作为一名科学家的发展。我将通过该奖项获得的知识和技术将发挥重要作用。实现我的职业目标并成为一名有效的独立调查员。