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: 8028618
• 负责人: Natalia Luisa Hiller
• 金额: $ 8.29万
• 依托单位: ALLEGHENY-SINGER RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8028618
• 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

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: The long-term goal of this proposal is the diagnosis and treatment of bacterial-induced ear infections. These infections are the most common illnesses in infants and young children.

描述（由申请人提供）：该提案包括1年的指导研究，以发展与中耳炎（OM）相关的微生物发病机制，然后在同一学科进行3年的独立研究。主要研究者在Kasturi Haldar博士的指导下在西北大学获得了免疫学和微生物发病学博士学位。作为她的论文工作的一部分，她确定了生物信息学与疟疾感染，极大地扩大了潜在的抗疟疾药物靶点池的新真核分泌组。她继续在Garth埃利希博士那里接受博士后研究员培训，在那里她将重点转向原核病原体，重点关注细菌诱导的中耳炎，并开发了一套用于比较基因组学的生物信息学工具，以确定基因型-表型相关性。她的工作揭示了临床沙门氏菌中非常广泛的基因组多样性。pneumoniae菌株，并且已经表明水平基因转移（HGT）是慢性多克隆S.肺炎感染。 现任提案中概述的行动计划将继续通过独特的教育机会整合来扩大她的科学技能;尖端设施和资源;以及基因组科学中心（CGS）提供的科学和指导专业知识。指导部分将在Garth埃利希博士的指导下进行。埃利希博士是CGS的执行董事，负责重大的范式转变，即培养阴性、耐药性慢性细菌感染是由代谢变化引起的，从抗生素到生物膜形式。他也是分布式基因组假说的作者，这是一个与生物膜概念相似的遗传学概念，并且是许多比较细菌基因组学工具的先驱。他培养了许多研究生，博士后研究员和初级教师。 科学和职业建议也将提供由CGS生物膜主任，博士J.威廉Costerton谁是皇家学会和美国微生物学会的研究员。此外，Costerton博士是现代生物膜范式（1978年）的创始人，也是微生物生物膜，生态学和多微生物群落许多方面的先驱研究者。Costerton博士获得了来自世界各地学生团体的众多硕士教师奖，并被公认为是发展和推进与他合作的初级科学家职业生涯的专家。 计算课程，生物信息学研讨会和科学会议，以及最近的多个合作项目的发展，其中一些已被纳入本项目的设计，将进一步提高PI的培训经验。与外部科学家的合作包括：1）开普敦大学的达伦·马丁博士，他是检测重组及其在进化中作用的专家; 2）密歇根大学的大卫谢尔曼博士，他是生化合成专家;第三章马里兰州大学的埃尔韦泰特林博士和诺华公司的克劳迪奥多纳蒂博士为比较基因组学开发了许多数学工具，并领导了这项工作创建通用的肺炎球菌注释系统; 4）Rockefeller的亚历山大托马斯博士和Universidade Nova de Lisboa的赫米尼亚德伦卡斯特博士，他们是肺炎球菌的发病机理和流行病学的权威，并收集了优秀的菌株库;和5）洛杉矶的加州大学的史文源博士，他开发了特异性靶向抗菌肽（STAMP）。 该候选人致力于细菌致病机理的研究，旨在改善细菌诱导的OM的诊断和治疗。该提案的重点是肺炎链球菌菌株（SP-1）的临床重要子集，这些菌株具有大流行性和耐药性。其目标是：1）开发一个S。本研究的目的是：1）建立一种新的SP-1特异性限制性修饰系统，研究其分子机制，并确定甲基转移酶抑制剂的治疗潜力;和3）研究新型SP-1羊毛硫抗生素-群体感应位点的作用机制，以及使用该位点内编码的肽靶向S.肺炎和治疗感染。CGS为这项工作提供了一个理想的环境，它将细菌生物膜、比较基因组学和中耳炎动物模型方面的专业知识与最先进的DNA测序、比较基因组杂交、计算生物学和共聚焦激光扫描显微镜设施相结合。 总之，该项目与CGS优秀的人员和设施资源相结合，将最大限度地发挥主要研究者建立科学利基的潜力，启动多项合作，在未来三年内申请NIH R 01资金，并开始在OM和相关慢性细菌感染的微生物学方面的独立职业生涯。 公共卫生相关性：该提案的长期目标是诊断和治疗细菌引起的耳部感染。这些感染是婴幼儿最常见的疾病。