Mechanisms of membrane biogenesis and peptidoglycan remodeling during sporulation

孢子形成过程中膜生物发生和肽聚糖重塑的机制

• 批准号: RGPIN-2015-04345
• 负责人: Tocheva, Elitza
• 金额: $ 3.14万
• 依托单位: University of British Columbia
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=765804
• 关键词: Mechanisms; membrane; biogenesis; peptidoglycan; remodeling

My research program seeks to understand the structural and functional changes that occur in the bacterial cell envelope during growth and cell division. Although bacteria occupy every niche in the biosphere and sustain life on this planet, they are faced with unpredictable environments. To survive, they have evolved a sophisticated, multilayered cell envelope structure composed of either one or two membranes and a mesh-like polymer (peptidoglycan) that protects them while allowing the selective passage of nutrients and waste products. Spatial and temporal regulation of changes in the cell envelope is essential to bacterial growth and division. Moreover, the bacterial cell envelope is a major target for antimicrobials. Thus, research into the bacterial cell envelope provides insight into fundamental biological processes and is critical for understanding human health and disease.Some bacteria have evolved mechanisms to protect their DNA from harsh environmental conditions by forming spores. These spores can remain viable for years without water or nutrients and can resist UV irradiation, heat, pH extremes and oxidative damage. Spore formation involves complex morphological changes in the membranes and peptidoglycan of single- and double-membraned bacteria and thus is ideal for studies of the bacterial cell envelope. In addition to being a useful model system, spore formation has significant implications for human health and disease. Examples of sporulating pathogenic bacteria include Bacillus cereus, which causes foodborne illness, Clostridium botulinum and C. tetani, the causative agents of botulism and tetanus, respectively, and Bacillus anthracis, which has been linked to bio-terrorism. Sporulating bacteria have been used for the production of antibiotics and enzymes, the delivery of vaccines and therapeutic agents, and the design of whole-cell biosensors. Interfering with the formation of a mature spore can help further develop better antimicrobial agents.By applying a range of approaches drawn from bioinformatics, molecular genetics, cell biology and structural biology with main emphasis on cryo electron tomography and super-resolution fluorescence light microscopy, I will characterize the structural and functional changes of the bacterial cell envelope during sporulation. Over the next five years, my research program will focus on characterizing two aspects of sporulation: 1) biogenesis of the outer membrane in double-membraned bacteria and 2) peptidoglycan remodeling in single- and double-membraned bacteria.

我的研究计划试图了解生长和细胞分裂过程中细菌细胞包膜中发生的结构和功能变化。尽管细菌占据了生物圈中的每个小众市场并在这个星球上维持生命，但它们面临着不可预测的环境。为了生存，它们已经进化出了一个由一个或两个膜和网状聚合物（肽聚糖）组成的复杂的多层细胞包膜结构，该结构可保护它们，同时允许养分和废物的选择性通过。细胞包膜变化的空间和时间调节对于细菌生长和分裂至关重要。此外，细菌细胞包膜是抗菌剂的主要靶标。因此，对细菌细胞包膜的研究提供了对基本生物学过程的见解，对于理解人类健康和疾病至关重要。一些细菌已经发展出通过形成孢子来保护其DNA免受恶劣环境条件的机制。这些孢子可以在没有水或养分的情况下保持活力数年，并且可以抵抗UV辐射，热，pH极端和氧化损伤。孢子的形成涉及单膜和双膜细菌的膜和肽聚糖的复杂形态变化，因此非常适合研究细菌细胞包膜。除了成为有用的模型系统外，孢子形成对人类健康和疾病具有重要意义。零散致病细菌的例子包括蜡状芽孢杆菌，蜡状芽孢杆菌，肉毒杆菌和肉毒杆菌和破伤风的病因，以及炭疽芽孢杆菌的病因分别导致食源性疾病，肉毒杆菌梭状芽胞杆菌和特氏梭菌，已与生物 - 特雷尔主义联系起来。散发细菌已用于生产抗生素和酶，疫苗和治疗剂的输送以及全细胞生物传感器的设计。干扰成熟孢子的形成可以帮助进一步发展更好的抗菌剂。通过采用从生物信息学，分子遗传学，细胞生物学和结构生物学中提取的一系列方法，主要强调了冷冻电子层析造影和超分辨率荧光显微镜，I将表征孢子形成过程中细菌细胞包膜的结构和功能变化。在接下来的五年中，我的研究计划将重点介绍孢子形成的两个方面：1）双膜细菌中外膜的生物发生，以及2）单膜和双膜细菌中的肽聚糖重塑。