BLR&D Research Career Scientist Award Application

BLR

• 批准号: 9339813
• 负责人: Gayatri Vedantam
• 金额: --
• 依托单位: SOUTHERN ARIZONA VA HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9339813
• 关键词: Acids; Adopted; Age; Anaerobic Bacteria; Animal Model; Antibiotic Therapy; Antibiotics; Arizona; Australia; Award; Bacteria; Bacterial Adhesins; Bacterial Infections; Basic Science; Biology; Canada; Cells; Centers for Disease Control and Prevention (U.S.); Clinical; Clostridium difficile; Disease; Elderly; Engineering; Enteral; Epidemic; Epidemiology; Evolution; Feedback; Flagella; France; Funding; Generations; Genes; Genetic; Goals; Healthcare; Healthcare Systems; Hospitalization; Hospitals; Human; Illinois; Immunity; Incidence; Individual; Infection; Intervention; Intestines; Knock-out; Knowledge; Laboratories; Legal patent; Mass Spectrum Analysis; Methodology; Microbial Biofilms; Military Personnel; Molecular; Monitor; Nature; Organism; Oxygen; Paper; Paris, France; Pathogenesis; Patients; Physicians; Polysaccharides; Population; Prevalence; Production; Proteomics; Publications; Reactive Oxygen Species; Recurrent disease; Research; Risk Factors; Role; Scientist; Seminal; System; Techniques; Testing; Therapeutic Agents; Time; Toxin; United States National Institutes of Health; Universities; Veterans; Virulence; Virulent; Work; capsule; career; cost effective; design; disorder prevention; enteric pathogen; epidemiology study; genome analysis; improved; innovation; methicillin resistant Staphylococcus aureus; mutant; novel; novel vaccines; pathogen; prevent; superoxide reductase; synthetic biology; tool; vaccine candidate

Project Summary/Abstract The overarching goal of our research is to understand the molecular basis of disease caused by enteric bacterial pathogens, and to leverage this knowledge to develop therapeutic agents that will benefit the Veteran population. A major focus of our laboratory is the study of the bacterial pathogen, Clostridium difficile, which causes healthcare-associated infections, and has been designated an “Urgent Threat” by the Centers for Disease Control and Prevention. The risk factors for acquiring C. difficile infection include age over 65 years, antibiotic treatment, and use of acid-suppressors; this combination of risk factors makes Veterans especially vulnerable to infection. Our ongoing epidemiological studies show that C. difficile infection rates in the Tucson VA (and other Arizona) hospitals are above the national average, and that many patients harbor `hyper-virulent' epidemic-associated strains of the pathogen. We have characterized VA C. difficile strains in detail, uncovered novel virulence strategies employed by these organisms, used cutting-edge genome analyses to track their evolution and spread, and provided feedback to physicians in an effort to reduce incidence of infections. We have also made several innovative advances in exploring the molecular mechanisms by which C. difficile causes disease. For these efforts, we have extensively used mass spectrometry techniques to globally analyze various strains to discern their unique virulence potential. Further, we have adopted, and greatly improved, recent methodologies to genetically manipulate C. difficile in order to understand its virulence; this has allowed us to knock out, or limit the expression of, various genes. Beyond the pioneering work revealing that C. difficile toxins contribute to disease, we have uncovered key roles for non-toxin factors including flagella, capsular polysaccharides and superoxide reductase in virulence. We have also used mass spectrometry to understand corresponding changes in host cells. Finally, building on our understanding of how C. difficile attaches to the host intestine, we recently designed and engineered a novel, safe “synthetic biologic” agent to express C. difficile adhesins. In an animal model of infection, the agent was able to completely block C. difficile infection and disease. This product, the first generation of which is fully supported by our current VA Merit award, is now protected by a provisional patent, and is currently under intensive further refinement. It is anticipated that the agent will be an effective, safe, “first-in-kind” non-antibiotic option to prevent C. difficile infection in Veterans, as well as all susceptible individuals.

项目摘要/摘要 我们研究的总体目标是了解疾病的分子基础 由肠细菌病原体引起，并利用这种知识发展 将使退伍军人人口受益的治疗剂。我们的主要重点 实验室是细菌病原体艰难梭菌的研究，这导致 与医疗保健相关的感染，已被指定为“紧急威胁” 疾病控制与预防中心。艰难梭菌的风险因素 感染包括65岁以上的年龄，抗生素治疗和使用酸抑制剂；这 风险因素的结合使退伍军人特别容易受到感染的影响。 我们正在进行的流行病学研究表明，图森的艰难梭菌感染率 VA（和其他亚利桑那州）医院高于全国平均水平，许多患者 病原体的港口“高刺”流行病相关菌株。我们有 详细表征了艰难梭菌菌株，发现了新的病毒策略 由这些生物使用，使用尖端的基因组分析来跟踪其进化 并传播，并向医生提供反馈，以减少 感染。 我们还在探索分子机制方面取得了一些创新的进步 艰难梭菌会引起疾病。对于这些努力，我们已经广泛使用了质量 光谱技术用于全球分析各种菌株以辨别其独特的 毒力潜力。此外，我们已经采用并大大改善了最近 为了理解其病毒，一种一般操纵艰难梭菌的方法； 这使我们能够淘汰或限制各种基因的表达。超越 开创性的工作表明，艰难梭菌毒素有助于疾病，我们发现了 非毒素因子的关键作用，包括鞭毛，囊囊多糖和 降低病毒的超氧化物。我们还使用质谱来理解 宿主细胞的相应变化。 最后，基于我们对艰难梭菌如何隶属宿主肠道的理解， 我们最近设计并设计了一种新型，安全的“合成生物学”代理，以表达C. 艰难的信封。在感染的动物模型中，药物能够完全阻止 艰难梭菌感染和疾病。该产品，第一代完全是 在我们当前的VA功绩奖的支持下，现在受到临时专利的保护， 目前正在深度进一步完善。预计代理人将是 有效，安全，“最初”的非抗生素选择，以防止艰难梭菌感染 退伍军人以及所有易感人士。