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Training in structural biology & glycobiology

结构生物学培训

基本信息

批准号：
8516743
负责人：
Hui Wu
金额：
$ 0.99万
依托单位：
IMPERIAL COLLEGE OF SCIENCE, TECHNOLOGY AND MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8516743
关键词：
3-Dimensional Adhesions Animal Model Area Bacterial Adhesins Bacterial Adhesion Bacterial Infections Biochemical Biogenesis Biological Models Biological Process Biology Cells Code Complex Enzymes Escherichia coli Event Family Gene Cluster Generations Genetic Genus staphylococcus Glycobiology Glycoproteins Goals Homologous Gene Laboratories Left Link London Mediating Microbial Biofilms Modeling Molecular Multienzyme Complexes Oral cavity Pathogenesis Pathway interactions Play Polysaccharides Protein Family Protein Glycosylation Protein Secretion Proteins Recombinants Research Research Personnel Research Project Grants Resolution Roentgen Rays Role Serine Site Streptococcus Streptococcus pneumoniae Structure Therapeutic Training Virulence Work X-Ray Crystallography career development college design experience fimbria fitness glycosylation glycosyltransferase interest new therapeutic target novel novel therapeutics oral streptococci pathogenic bacteria polypeptide programs structural biology sugar three dimensional structure

项目摘要

Project Summary Bacterial adhesion and colonization are crucial for bacterial fitness and virulence. Despite the great progress has been made in understanding of this critical biological process, molecular details are largely unknown. Our pioneer studies of a streptococcal fimbriae-associated protein (Fap1) in a model organism, Streptococcus parasanguinis have revealed a new family of bacterial adhesins, serine-rich repeat glycoproteins (SRRPs). This family of proteins is synthesized by a gene cluster coding for glycosyltransferaes and accessory secretion proteins; they are highly conserved in pathogenic streptococci and staphylococci, and play important roles in bacterial interaction with the host cells and pathogenesis. Genetic and biochemical studies have led us to conclude that glycosylation of Fap1 is initiated by a two enzyme heterodimeric complex that is composed by two putative glycosyltransferases Gtf1 and Gtf2. The Gtf complex catalyzes the transfer of GlcNAc to the serine-rich sites of Fap1. Dr. Wu will use his sabbatical leave to obtain training in structural biology and glycobiology to further explore molecular details regarding biogenesis of SRRPs. The proposed training will take place in Imperial College London in Dr. Steve Matthews and Dr. Anne Dell¿s laboratories. Drs. Matthews and Dell are the leading experts in their field, and very interested in Dr. Wu¿s research area and have already collaborated with Dr. Wu in the past on different research projects. Training in their laboratories would allow the PI have better understanding of structural biology and glycobiology, and help the PI apply this state of art research approaches in his current research and develop new research programs which explore functional contribution of SRRPs to pathogenic streptococci and staphylococci. The PI¿s long-term goals are to determine how biogenesis of SRRPs contributes to bacterial virulence and how we can harness the new pathway to design therapeutics. Specific Aim 1: Obtain training in structural biology by solving 3-D high resolution structure of glycosyltransferases that are involved in glycosylation of SRRPs. Dr. Wu will spend 3-4 months on this specific aim. Specific Aim 2: Obtain training in glycobiology by charactering glycan structures attached to SRRPs. Dr. Wu will spend 3-4 months on this specific aim. As SRRPs are highly conserved in pathogenic streptococci and staphylococci, deciphering the molecular events that modulates their biogenesis will not only help us to understand biology of the plaque formation in the oral cavity but also provide new information useful for the design of novel therapeutic targets towards bacterial infections mediated by SRRPs, a new research direction for the PI.

项目概要细菌粘附和定植对于细菌的适应性和毒力至关重要。尽管在理解这一关键的生物过程方面已经取得了巨大进展，但分子细节在很大程度上仍是未知的。我们对模型生物副血链球菌中的链球菌菌毛相关蛋白 (Fap1) 进行的开创性研究揭示了一个新的细菌粘附素家族，即富含丝氨酸的重复糖蛋白 (SRRP)。该蛋白家族由编码糖基转移蛋白和辅助分泌蛋白的基因簇合成。它们在致病性链球菌和葡萄球菌中高度保守，在细菌与宿主细胞的相互作用和发病机制中发挥重要作用。遗传和生化研究使我们得出结论，Fap1 的糖基化是由双酶异二聚体复合物启动的，该复合物由两种假定的糖基转移酶 Gtf1 和 Gtf2 组成。 Gtf 复合物催化 GlcNAc 转移至 Fap1 富含丝氨酸的位点。吴博士将利用休假时间接受结构生物学和糖生物学方面的培训，以进一步探索有关 SRRP 生物发生的分子细节。拟议的培训将在伦敦帝国学院 Steve Matthews 博士和 Anne Dell 博士的实验室中进行。博士。 Matthews和Dell是各自领域的顶尖专家，对吴博士的研究领域非常感兴趣，并且过去已经与吴博士在不同的研究项目上进行过合作。在他们的实验室进行培训将使 PI 更好地了解结构生物学和糖生物学，并帮助 PI 在当前的研究中应用这种最先进的研究方法，并开发新的研究项目，探索 SRRP 对致病性链球菌和葡萄球菌的功能贡献。 PI 的长期目标是确定 SRRP 的生物发生如何影响细菌毒力，以及我们如何利用新途径来设计治疗方法。具体目标 1：通过解析参与 SRRP 糖基化的糖基转移酶的 3-D 高分辨率结构，获得结构生物学方面的培训。吴博士将花费3-4个月的时间来实现这个具体目标。具体目标 2：通过表征 SRRP 附着的聚糖结构来获得糖生物学培训。吴博士将花费3-4个月的时间来实现这个具体目标。由于SRRP在致病性链球菌和葡萄球菌中高度保守，破译调节其生物发生的分子事件不仅有助于我们了解口腔菌斑形成的生物学，而且还为设计针对SRRP介导的细菌感染的新治疗靶点提供有用的新信息，这是PI的新研究方向。