BLR&D Research Career Scientist Award Application

BLR

• 批准号: 9898229
• 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/9898229
• 关键词: Acids; Adopted; Age; Anaerobic Bacteria; Animal Model; Antibiotic Therapy; Antibiotics; Arizona; Australia; Award; Bacteria; Bacterial Adhesins; Bacterial Infections; Basic Science; Biological; Biological Products; 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 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; comorbidity; cost effective; design; enteric pathogen; epidemiology study; genetic manipulation; genome analysis; healthcare-associated infections; human old age (65+); improved; infection rate; innovation; methicillin resistant Staphylococcus aureus; mutant; novel; novel vaccines; pathogen; pathogenic bacteria; 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.

项目概要/摘要 我们研究的首要目标是了解疾病的分子基础 由肠道细菌病原体引起，并利用这些知识来开发 将使退伍军人群体受益的治疗剂。我们的一个主要重点 实验室是对细菌病原体艰难梭菌的研究，它会导致 医疗保健相关感染，并已被指定为“紧急威胁” 疾病控制和预防中心。感染艰难梭菌的风险因素 感染包括年龄超过 65 岁、抗生素治疗和使用抑酸剂；这 多种危险因素的结合使退伍军人特别容易受到感染。 我们正在进行的流行病学研究表明，图森地区的艰难梭菌感染率 弗吉尼亚州（和亚利桑那州其他地区）的医院高于全国平均水平，而且许多患者 含有与流行病相关的“高毒力”病原体菌株。我们有 详细描述了 VA 艰难梭菌菌株的特征，发现了新的毒力策略 这些生物体使用尖端的基因组分析来追踪它们的进化 并传播，并向医生提供反馈，以努力减少发病率 感染。 我们在探索分子机制方面也取得了多项创新进展 艰难梭菌由此引起疾病。为了这些努力，我们广泛使用了质量 光谱分析技术可对各种菌株进行全局分析，以辨别其独特性 潜在的毒力。此外，我们采用并大大改进了最近的 对艰难梭菌进行基因操作以了解其毒力的方法； 这使我们能够敲除或限制各种基因的表达。超越 我们发现，艰难梭菌毒素导致疾病的开创性工作 非毒素因子（包括鞭毛、荚膜多糖和 超氧化物还原酶具有毒力。我们还使用质谱分析来了解 宿主细胞发生相应的变化。 最后，基于我们对艰难梭菌如何附着在宿主肠道上的理解， 我们最近设计并制造了一种新型、安全的“合成生物”制剂来表达艰难梭菌。 艰难梭菌粘附素。在感染动物模型中，该药物能够完全阻断 艰难梭菌感染和疾病。该产品第一代完全 受到我们当前 VA 优异奖的支持，现已受到临时专利的保护，并且 目前正在紧锣密鼓地进一步完善中。预计代理将是 有效、安全、“同类首创”的非抗生素选择，可预防艰难梭菌感染 退伍军人以及所有易感人群。