Insights from Comparative Genomics for the Treatment of Pneumococcal Infections

比较基因组学对肺炎球菌感染治疗的见解

• 批准号: 8539870
• 负责人: Natalia Luisa Hiller
• 金额: $ 24.9万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8539870
• 关键词: Acute; American; Animal Model; Antibiotic Resistance; Antimalarials; Award; Bacterial Infections; Bacteriophages; Biochemical; Bioinformatics; California; Candidate Disease Gene; Child; Chronic; Clinical; Collaborations; Communities; Computational Biology; DNA; DNA Restriction-Modification Enzymes; DNA Sequencing Facility; Detection; Development; Diagnosis; Diagnostic; Discipline; Disease; Drug Delivery Systems; Drug resistance; Ecology; Educational workshop; Epidemiology; Evolution; Faculty; Funding; Gene Chips; Generations; Genetic; Genetic Recombination; Genome; Genomics; Genotype; Goals; Horizontal Gene Transfer; Human Resources; Immunology; In Vitro; Infant; Infection; Laser Scanning Confocal Microscopy; Lead; Libraries; Light; Los Angeles; Maryland; Mentors; Mentorship; Metabolic; Methylation; Methyltransferase; Michigan; Microbial Biofilms; Microbiology; Molecular; Otitis Media; Otitis Media with Effusion; Outcome; Pathogenesis; Patients; Peptides; Phenotype; Play; Pneumococcal Infections; Postdoctoral Fellow; Principal Investigator; Regulation; Research; Research Personnel; Resources; Risk; Role; SP1 gene; Science; Scientist; Societies; Specialist; Streptococcus pneumoniae; Students; System; Training; United States National Institutes of Health; Universities; Virulence; Work; antimicrobial; authority; career; comparative; comparative genomic hybridization; comparative genomics; cost effective; design; disease phenotype; ear infection; experience; graduate student; improved; in vivo; inhibitor/antagonist; insight; killings; meetings; microbial; novel; outcome forecast; pandemic disease; pathogen; quorum sensing; research and development; restriction enzyme; skills; teacher; therapy design; tool

7. Project Summary This proposal consists of 1 year of mentored research for the development of a career in microbial pathogenesis as it relates to otitis media (OM), followed by 3 years of independent research in the same discipline. The principal investigator completed a doctorate in Immunology and Microbial Pathogenesis at Northwestern University under the mentorship of Dr. Kasturi Haldar. As part of her dissertation work she identified bioinformatically a novel eukaryotic secretome associated with malarial infection that has vastly expanded the pool of potential anti-malarial drug targets. She continued her training as a post-doctoral fellow with Dr. Garth Ehrlich, where she switched her emphasis to prokaryotic pathogens focusing on bacterially- induced otitis media and the development of a suite of bioinformatic tools for comparative genomics to identify genotype-phenotype correlations. Her work has exposed the very extensive genomic diversity among clinical S. pneumoniae strains, and has shown that horizontal gene transfer (HGT) is the major mechanism of diversity generation during chronic polyclonal S. pneumoniae infections. The plan of action outlined in the incumbent proposal will continue to expand her scientific skills through a unique integration of educational opportunities; cutting-edge facilities and resources; and scientific and mentoring expertise available at the Center for Genomic Sciences (CGS). The mentored section will be carried out under the guidance of Dr. Garth Ehrlich. Dr. Ehrlich is the Executive Director of the CGS, and is responsible for the major paradigm shift that states that culture-negative, antibiotic-resistant chronic bacterial infections result from a metabolic change from a planktonic to a biofilm form. He is also the author of the Distributed Genome Hypothesis, a genetic parallel to the biofilm concept and is the pioneer of many of the tools of comparative bacterial genomics. He has trained numerous graduate students, postdoctoral fellows, and junior faculty. Scientific and career advice will also be provided by the CGS Biofilm Director, Dr. J. William Costerton who is a fellow of the Royal Society and of the American Society for Microbiology. Moreover, Dr. Costerton is the originator of the modern biofilm paradigm (1978), and a pioneer researcher in many aspects of microbial biofilms, ecology, and polymicrobial communities. Dr. Costerton has received numerous master teacher awards from student groups around the world and is recognized as an expert in developing and advancing the careers of junior scientists with whom he works. Computational coursework, a bioinformatic workshop, and scientific meetings, as well as the development of multiple recent collaborations, some of which have been incorporated into this project's design, will further enhance the PI's training experience. Collaborations with outside scientists include: 1) Dr. Darren Martin at Cape Town University, an expert in the detection of recombination and it's role in evolution; 2) Dr. David Sherman at the University of Michigan, a specialist in biochemical synthesis; 3) Drs. Herve Tettelin at the University of Maryland and Claudio Donati at Novartis who have developed many mathematical tools for comparative genomics and led the effort to create a universal pneumococcal annotation system; 4) Drs. Alexander Tomasz at the Rockefeller and Dr. Herminia de Lencastre at the Universidade Nova de Lisboa who are authorities on the pathogenesis and epidemiology of pneumococcus and who have collected an outstanding library of strains; and 5) Dr. Wenyuan Shi at University of California in Los Angeles who has developed specifically targeted anti-microbial peptides (STAMPs). The candidate is devoted to a career in bacterial pathogenesis designed to improve the diagnosis and treatment of bacterially-induced OM. The focus of this proposal is on a clinically important subset of Streptococcus pneumoniae strains (the SP-1) that are pandemic and drug resistant. The aims are to: 1) develop an S. pneumoniae supragenome gene chip to provide a high-throughput and cost-effective means to perform comparative genomic hybridizations (CGH) on large numbers of clinical isolates, and ultimately to function as a molecular diagnostic to guide treatment of OM; 2) investigate the molecular mechanism of a novel SP-1-specific restriction-modification system, and determine the treatment potential of using inhibitors to block the methyltransferase; and 3) investigate the mechanism of action of an novel SP-1 lantibiotic-quorum sensing locus, and the potential to use a peptide encoded within this locus to target anti-microbials to S. pneumoniae and treat infections. The CGS provides an ideal setting for this work by combining expertise in bacterial biofilms, comparative genomics, and otitis media animal models, with a state-of-the-art facilities for DNA sequencing, comparative genomic hybridization, computational biology, and confocal laser scanning microscopy. In summary, this project, combined with the outstanding personnel and facilities resources available at the CGS, will maximize the potential for the principal investigator to establish a scientific niche, initiate multiple collaborations, apply for NIH R01 funding within the next three years, and commence an independent career in the microbiology of OM and related chronic bacterial infections.

七、项目概要 该提案包括为期 1 年的微生物职业发展指导研究 与中耳炎 (OM) 相关的发病机制，随后针对同一领域进行了 3 年的独立研究 纪律。主要研究者在以下大学完成了免疫学和微生物发病机制的博士学位 西北大学在 Kasturi Haldar 博士的指导下。作为她论文工作的一部分，她 通过生物信息学鉴定了一种与疟疾感染相关的新型真核分泌组，该组具有极大的 扩大了潜在的抗疟疾药物靶标库。她继续接受博士后研究员的培训 与 Garth Ehrlich 博士合作，她将重点转向原核病原体，重点关注细菌- 诱发中耳炎并开发一套用于比较基因组学的生物信息学工具来识别 基因型-表型相关性。她的工作揭示了临床中非常广泛的基因组多样性 肺炎链球菌菌株，并已表明水平基因转移（HGT）是多样性的主要机制 慢性多克隆肺炎链球菌感染期间的产生。 现有提案中概述的行动计划将继续通过以下方式扩展她的科学技能： 独特的教育机会整合；尖端的设施和资源；以及科学和 基因组科学中心 (CGS) 提供指导专业知识。指导部分将进行 在 Garth Ehrlich 博士的指导下。 Ehrlich 博士是 CGS 的执行董事， 负责重大范式转变，即培养阴性、抗生素耐药的慢性细菌 感染是由从浮游形式到生物膜形式的代谢变化引起的。他也是该书的作者 分布式基因组假说，与生物膜概念平行的遗传学概念，是许多理论的先驱 比较细菌基因组学工具。他培养了多名研究生、博士后、 和初级教师。 CGS 生物膜总监 J. William Costerton 博士也将提供科学和职业建议 他是英国皇家学会和美国微生物学会的会员。此外，科斯特顿博士 现代生物膜范式的创始人（1978），微生物学许多方面的先驱研究者 生物膜、生态学和多微生物群落。 Costerton博士曾获得众多名师指导 获得世界各地学生团体的奖项，并被公认为开发和推进 与他一起工作的初级科学家的职业生涯。 计算课程、生物信息学研讨会和科学会议，以及 最近多项合作的发展，其中一些已纳入该项目的设计中， 将进一步提升PI的培训经验。与外部科学家的合作包括：1) Darren 博士 开普敦大学的马丁，重组检测及其在进化中的作用方面的专家； 2）博士。 David Sherman，密歇根大学生化合成专家； 3）博士。埃尔夫·泰特林 (Herve Tettelin) 马里兰大学和诺华公司的克劳迪奥·多纳蒂（Claudio Donati）开发了许多数学工具 比较基因组学并领导创建通用肺炎球菌注释系统的工作； 4）博士。 洛克菲勒大学的亚历山大·托马斯 (Alexander Tomasz) 和新里斯本大学 (Universidade Nova de Lisboa) 的赫米尼亚·德·伦卡斯特 (Herminia de Lencastre) 博士 是肺炎球菌发病机制和流行病学方面的权威，并收集了 优秀的菌株库； 5) 加州大学洛杉矶分校史文元博士 开发了专门针对微生物的肽（STAMP）。 候选人致力于细菌发病机制的职业生涯，旨在改善诊断和 治疗细菌诱导的 OM。该提案的重点是临床上重要的一个子集 肺炎链球菌菌株 (SP-1) 具有大流行性和耐药性。目标是：1) 开发肺炎链球菌超基因组基因芯片，以提供高通量且经济高效的手段 对大量临床分离株进行比较基因组杂交（CGH），并最终 作为分子诊断来指导 OM 的治疗； 2）研究分子机制 新型 SP-1 特异性限制性修饰系统，并确定使用抑制剂的治疗潜力 阻断甲基转移酶； 3) 研究新型 SP-1 羊毛硫抗生素群体的作用机制 传感位点，以及使用该位点内编码的肽将抗菌剂靶向金黄色葡萄球菌的潜力。 肺炎并治疗感染。 CGS 结合了以下方面的专业知识，为这项工作提供了理想的环境： 细菌生物膜、比较基因组学和中耳炎动物模型，拥有最先进的设施 DNA 测序、比较基因组杂交、计算生物学和共焦激光扫描 显微镜。 总之，该项目结合了优秀的人员和设施资源 CGS 将最大限度地发挥主要研究者建立科学利基的潜力，发起多项 合作，在未来三年内申请NIH R01资助，并开始独立职业生涯 OM 的微生物学和相关的慢性细菌感染。