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: 8518046
• 负责人: Natalia Luisa Hiller
• 金额: $ 23.14万
• 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/8518046
• 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 Targeting; 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.

7.项目总结 这份提案包括为期一年的微生物职业发展指导研究。 与中耳炎(OM)有关的发病机制，随后对此进行了3年的独立研究 纪律。首席研究员完成了免疫学和微生物致病学博士学位 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 生物信息学鉴定了一种与疟疾感染相关的新的真核分泌组 扩大了潜在的抗疟疾药物靶标库。她继续作为博士后研究员接受培训 与Garth Ehrlich博士合作，她将重点转向原核病原体，重点放在细菌- 诱发性中耳炎和一套用于比较基因组学鉴定的生物信息学工具的开发 基因型与表型的相关性。她的工作揭示了临床中非常广泛的基因组多样性 并表明水平基因转移(HGT)是导致多样性的主要机制。 在慢性多克隆肺炎链球菌感染期间产生。 现任提案中概述的行动计划将通过以下方式继续扩大她的科学技能 独特的教育机会、尖端设施和资源以及科学和 基因组科学中心(CGS)提供的指导专业知识。指导部分将进行 在加思·埃尔利希博士的指导下出院。埃尔利希博士是CGS的执行董事， 负责重大的范式转变，即培养阴性、抗生素耐药的慢性细菌 感染是由于新陈代谢从浮游生物转变为生物膜造成的。他也是《 分布式基因组假说，一种与生物膜概念类似的遗传假说，是许多 比较细菌基因组学的工具。他培养了无数的研究生，博士后研究员， 和初级教员。 CGS生物膜主任J.William Costerton博士也将提供科学和职业建议 他是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)，微生物许多方面的先驱研究人员 生物膜、生态和多微生物群落。科斯特顿博士曾接待过无数的名师 来自世界各地的学生团体的奖项，并被公认为开发和推动 与他共事的初级科学家的职业生涯。 计算课程，生物信息学研讨会，科学会议，以及 开发最近的多个合作项目，其中一些已纳入该项目的设计中， 将进一步提升私家侦探的训练经验。与外部科学家的合作包括：1)达伦博士 开普敦大学的马丁博士是检测重组及其在进化中的作用的专家； 密歇根大学的大卫·谢尔曼，生化合成专家；3)赫夫·泰特林博士 马里兰大学和诺华公司的克劳迪奥·多纳蒂，他们开发了许多数学工具 比较基因组学，并领导了创建通用肺炎球菌注释系统的努力； 洛克菲勒的亚历山大·托马兹和里斯本大学的赫米尼亚·德·伦卡斯特博士 是肺炎球菌的发病机制和流行病学方面的权威人士，以及谁收集了 杰出的菌株文库；以及5)洛杉矶加州大学的施文元博士，他拥有 开发了专门针对微生物的抗菌肽(STAMP)。 应聘者致力于细菌发病机制方面的职业生涯，旨在提高诊断和 细菌性肠炎的治疗。这项建议的重点是临床上重要的子集 具有大流行和抗药性的肺炎链球菌菌株(SP-1)。目标是：1) 开发肺炎链球菌超基因组基因芯片，提供高通量和高成本效益的手段 对大量临床分离株进行比较基因组杂交(CGH)，并最终 作为一种分子诊断手段来指导OM的治疗；2)探讨 新的SP-1特异性限制-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抗生素Quorum的作用机制 感测基因座，以及利用该基因座内编码的多肽靶向抗S。 肺炎和治疗感染。CGS通过结合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、计算生物学和激光共聚焦扫描 显微镜。 总而言之，这个项目，加上现有的优秀人员和设施资源， CGS，将最大限度地发挥首席调查员的潜力，建立一个科学利基，启动多个 合作，在未来三年内申请NIH R01资金，并在 OM的微生物学和相关的慢性细菌感染。