A Rationally Targeted Approach to Preventing GBS Infection

预防 GBS 感染的合理针对性方法

基本信息

批准号：
10076140
负责人：
Thomas A Hooven
金额：
$ 19万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-02-05 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10076140
关键词：
Amniotic Fluid Animal Model Antibodies Antigens Bacterial Infections Basic Science Binding Bioinformatics Biological Blood Data Development Disease Essential Genes Exposure to Flow Cytometry Genes Genome Goals Growth Health Human Immune Immunization Immunology In Vitro Infection Interferon Type II Interleukin-17 K-Series Research Career Programs Knock-out Knowledge Laboratories Libraries Liquid substance Mediating Mentors Mentorship Methods Modeling Molecular Genetics Mus Neonatal Neonatal Mortality Oryctolagus cuniculus Outcome PAWR protein Pathogenesis Pediatrics Perinatal Infection Polysaccharides Prevention Prevention strategy Proteins Publishing Research Research Personnel Scientific Advances and Accomplishments Sepsis Serotyping Serum Societies Solid Specificity Streptococcus Group B Surface System T cell response T-Cell Activation Techniques Technology Testing Training Universities Vaccination Vaccines Vagina Work base clinically relevant early onset efficacy testing experimental study fetal infection fitness gene product genome wide screen genome-wide genomic locus human disease improved in vivo in vivo Model infection risk insight intraamniotic infection mortality mouse model mutant neonatal morbidity neonatal period neonatal sepsis next generation sequencing novel novel strategies novel vaccines pathogen peripheral blood polyclonal antibody prevent professor programs reproductive tract screening translational research program transposon sequencing vaccine candidate vaccine development vaccine efficacy whole genome

项目摘要

PROJECT SUMMARY Dr. Thomas Hooven is a neonatologist and Assistant Professor of Pediatrics at Columbia University studying Streptococcus agalactiae (group B Streptococcus; GBS), the major infectious cause of neonatal morbidity and mortality. His research, under the mentorship of Dr. Adam Ratner, focuses on genes and gene networks that enable GBS to successfully colonize the maternal reproductive tract and to survive in amniotic fluid and blood during perinatal infection. Using a novel genome-wide screening technique based on next-generation sequencing of transposon-genome junctions from a saturated mutant library (Tn-seq), Dr. Hooven can accurately predict GBS genes whose protein products are necessary for bacterial growth under diverse experimental conditions. His proposed research seeks to use Tn-seq technology—in combination with ex vivo and in vivo models of colonization and invasion—to pinpoint surface-localized GBS proteins whose functions are essential for pathogenesis. Once validated by targeted knockout and antibody coincubation experiments, those proteins identified as essential for pathogenesis will be purified and tested as candidate vaccines to prevent vaginal colonization, ascending chorioamnionitis, and early-onset sepsis in clinically relevant mouse models. Recognizing that vaccine efficacy may depend on a combination of humoral and cellular immune mechanisms, this proposal also includes studies of opsonophagocytosis after antibody binding to candidate vaccine protein targets and T cell responses to immunization and vaginal colonization. By performing this research, Dr. Hooven will advance scientific understanding of GBS pathogenesis and bring society closer to a safe and effective vaccine to prevent devastating neonatal GBS infections. He will also expand his experimental repertoire through exposure to key methods in bioinformatics, immunology, molecular genetics, and vaccine development. This project will provide crucial training that will set the stage for his transition to becoming an independent investigator. Upon completion of the proposed research, Dr. Hooven will be ready to assume oversight of his own basic and translational research program aimed at advancing neonatal health through new insights into infection and new approaches toward its prevention and treatment.

项目摘要托马斯·胡文（Thomas Hooven）博士是哥伦比亚大学研究的新生儿学家和儿科助理教授链球菌agalactiae（B组链球菌； GBS），这是新生儿发病率和死亡。在亚当·拉特纳（Adam Ratner）博士的心态下，他的研究专注于基因和基因网络使GB能够成功地定居于孕产妇生殖道并在羊水和血液中生存在围产期感染期间。使用基于下一代的新型全基因组筛查技术来自饱和突变库（TN-Seq）的转座子基因组连接的测序，Hooven博士可以准确预测其蛋白质产物在潜水员下生长必不可少的GBS基因实验条件。他提出的研究旨在使用TN-Seq技术 - 与Ex Vivo结合以及定植和侵袭的体内模型 - 查明表面定位的GBS蛋白的功能对于发病机理至关重要。一旦通过靶向敲除和抗体重合实验来验证，那些被鉴定为发病机理必不可少的蛋白质将被纯化和测试为候选疫苗在临床相关小鼠中预防阴道定殖，上升绒毛膜炎和早发败血症型号。认识到疫苗效率可能取决于体液和细胞免疫的组合机制，该建议还包括抗体与候选者结合后的脑吞噬作用的研究疫苗蛋白靶标和T细胞对免疫抑制和阴道定植的反应。通过进行这项研究，Hooven博士将提高对GBS发病机理的科学理解，并带来社会更接近安全有效的疫苗，以防止毁灭性的新生儿GBS感染。他也会通过暴露于生物信息学，免疫学，分子的关键方法，扩大他的实验曲目遗传学和疫苗开发。该项目将提供关键的培训，为他的过渡到成为独立研究者。拟议的研究完成后，Hooven博士将准备对自己的基本和翻译的研究计划进行监督，以促进新生儿健康通过对感染的新见解以及预防和治疗的新方法。