Training in structural biology & glycobiology

结构生物学培训

• 批准号: 8452914
• 负责人: Hui Wu
• 金额: $ 5.42万
• 依托单位: IMPERIAL COLLEGE OF SCIENCE, TECHNOLOGY AND MEDICINE
• 依托单位国家: 美国
• 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/8452914
• 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

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Using structural biology and glycobiology approaches to explore a conserved glycosylation and secretion pathway in oral streptococci and pathogenic streptococci will allow us to uncover new targets with therapeutic potentials, thus the training in the proposed areas of research will allow the PI to develop new research programs, and promote scientific discovery and the PI's career development.

描述（由申请方提供）：细菌粘附和定植对于细菌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取得了很大进展，但分子细节在很大程度上是未知的。我们的先驱研究链球菌菌毛相关蛋白（Fap 1）在模式生物，链球菌副血揭示了一个新的家庭的细菌粘附素，富含丝氨酸的重复糖蛋白（SRRP）。该蛋白家族由编码糖基转移酶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，并且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。遗传和生物化学研究使我们得出结论，Fap 1的糖基化是由两种酶异二聚体复合物引发的，该复合物由两种推定的糖基转移酶Gtf 1和Gtf 2组成。Gtf复合物催化GlcNAc转移到Fap 1的富含丝氨酸的位点。吴博士将利用他的公休假， 结构生物学和糖生物学，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理工学院的史蒂夫马修斯博士和安妮戴尔博士的实验室进行。马修斯博士和戴尔博士是各自领域的顶尖专家，对吴博士的研究领域非常感兴趣，过去曾与吴博士在不同的研究项目上合作。在他们的实验室进行培训将使PI更好地理解结构生物学和糖生物学，并帮助PI在其当前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的生物发生如何促进细菌毒力，以及我们如何利用新途径设计治疗方法。具体目标1：通过解决参与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3-4个月的时间来实现这一目标。具体目标2：通过表征连接到SRRP的聚糖结构，获得糖生物学培训。吴博士将花3-4个月的时间来实现这一目标。由于SRRP在致病性链球菌和葡萄球菌中高度保守，因此破译调节其生物发生的分子事件不仅有助于我们理解口腔中斑块形成的生物学，而且还为设计针对SRRP介导的细菌感染的新型治疗靶点提供了新的信息，这是PI的一个新的研究方向。 公共卫生相关性：使用结构生物学和糖生物学方法来探索口腔链球菌和致病性链球菌中保守的糖基化和分泌途径将使我们能够发现具有治疗潜力的新靶点，因此， 建议的研究领域将允许PI开发新的研究计划，并促进科学发现和PI的职业发展。