BLRD Research Career Scientist Award Application

BLRD 研究职业科学家奖申请

• 批准号: 10337064
• 负责人: Andres Vazquez-Torres
• 金额: --
• 依托单位: VA EASTERN COLORADO HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-10-01 至 2025-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10337064
• 关键词: Alzheimer' s Disease; Amino Acids; Aminoglycoside resistance; Aminoglycosides; Anabolism; Antibiotic Resistance; Antibiotics; Award; Bacteremia; Bacteria; Bacterial Antibiotic Resistance; Binding; Blood; Burkholderia pseudomallei; Cell Wall; Cell division; Centers for Disease Control and Prevention (U.S.); Cessation of life; Clinical; Collaborations; Colorado; Complex; Complication; Cytochromes; DNA-Directed RNA Polymerase; Development; Diarrhea; Electron Transport; Enzymes; Escherichia coli; Evolution; Excretory function; Faculty; Family; Fostering; Funding; Genetic Transcription; Goals; Grant; Growth; Guanosine Tetraphosphate; HIV; Health; Healthcare Systems; Immunologic Deficiency Syndromes; Individual; Infection; Inflammation Mediators; International; Investigation; Journals; Knowledge; Legal patent; Mediating; Mediator of activation protein; Medical center; Mentors; Metabolic; Metabolic Pathway; Metabolism; Military Personnel; Mission; Molecular; Monitor; Monobactams; Multi-Drug Resistance; NADPH Oxidase; NOS2A gene; Nature; Nitric Oxide; Nucleotides; Oxidation-Reduction; Paper; Parkinson Disease; Pathogenesis; Patients; Persons; Phagocytes; Pharmaceutical Preparations; Play; Poison; Poisoning; Postdoctoral Fellow; Protein Biosynthesis; Proteins; Publishing; Purines; Regulation; Reporting; Research; Research Personnel; Research Project Grants; Resistance; Rod; Role; Salmonella; Salmonella infections; Sampling; Schedule; Science; Scientist; Secondary to; Seminal; Site; System; Training; Transcriptional Elongation Factors; Translating; Translations; Tubulin; Type III Secretion System Pathway; United States Department of Veterans Affairs; Universities; Veterans; Virulence; Wisconsin; Work; World Health Organization; absorption; antibiotic tolerance; antimicrobial; base; beta-Lactams; career; enteric pathogen; fundamental research; global health; graduate student; improved; macrophage; microbial; misfolded protein; next generation; novel; novel therapeutics; pathogen; pathogenic bacteria; preclinical study; programs; rational design; response; training opportunity; transcription factor

Salmonella infections are responsible for an estimated 3 million annual deaths worldwide. Multidrug resistance among clinical Salmonella more than doubled from 2011 to 2013. The World Health Organization has ranked Salmonella as one of the top 12 antibiotic resistant bacterial threats to global health. The goal of this Research Career Scientist Award is to continue with our efforts to apply our knowledge of Salmonella virulence to the development of novel antibiotics against multidrug resistant bacterial pathogens. Resistance of Salmonella and other pathogenic bacteria to antibiotics is in great part regulated by the nucleotide alarmone guanosine tetraphosphate and the DksA protein. Both of these mediators bind to the secondary channel of RNA polymerase, regulating transcription of central metabolic pathways and a variety of virulence programs. We will carry on our research on the molecular mechanisms by which guanosine tetraphosphate and DksA regulate Salmonella transcriptional programs. The Research Career Scientist Award will also allow us to develop novel antibiotics that inhibit DksA-dependent bacterial transcription. Binding of DksA to the secondary channel of RNA polymerase is in competition with Gre transcription elongation factors. We have found that Gre proteins are needed for Salmonella virulence and the resistance of this Gram-negative rod to antibiotics. We plan to characterize the molecular mechanisms by which Gre factors promote bacterial pathogenesis and antibiotic resistance. These research projects are highly collaborative in nature, involving scientific interactions with investigators at the Veterans Affairs Eastern Colorado Healthcare System, the Atlanta VA Medical Center and the Veterans Administration Ann Arbor Healthcare System. I plan to continue fostering these productive collaborations. Training of junior faculty, graduate students and postdoctoral fellows are also important components of this Research Career Scientist Award. Moreover, in collaboration with other investigators at the at the Veterans Affairs Eastern Colorado Healthcare System and Wisconsin-Madison VA Medical Center, we will continue mentoring promising CDA- 2 candidates, and thus help train the next generation of outstanding VA scientists.

沙门氏菌感染估计每年导致全世界 300 万人死亡。多药 2011 年至 2013 年，临床沙门氏菌的耐药性增加了一倍多。世界卫生组织 该组织将沙门氏菌列为全球 12 大抗生素耐药性细菌威胁之一 健康。该研究职业科学家奖的目标是继续努力应用我们的研究成果 沙门氏菌毒力知识对开发抗多重耐药性新型抗生素的影响 细菌病原体。 沙门氏菌和其他病原菌对抗生素的耐药性在很大程度上受到 核苷酸报警素四磷酸鸟苷和 DksA 蛋白。这两个中介都绑定到 RNA聚合酶的二级通道，调节中央代谢途径的转录和 各种毒力程序。我们将继续研究其分子机制 四磷酸鸟苷和 DksA 调节沙门氏菌转录程序。研究 职业科学家奖还将使我们能够开发出抑制 DksA 依赖性的新型抗生素 细菌转录。 DksA 与 RNA 聚合酶二级通道的结合是竞争性的 与 Gre 转录延伸因子。我们发现沙门氏菌需要 Gre 蛋白 这种革兰氏阴性杆菌的毒力和对抗生素的耐药性。我们计划描述 Gre 因子促进细菌发病机制和抗生素耐药性的分子机制。 这些研究项目本质上是高度协作的，涉及与 科罗拉多州东部退伍军人事务部医疗系统、亚特兰大退伍军人管理局医疗中心的调查人员 中心和退伍军人管理局安娜堡医疗系统。我打算继续培养 这些富有成效的合作。初级教师、研究生和博士后的培训 也是该研究职业科学家奖的重要组成部分。此外，在合作中 与东科罗拉多医疗系统退伍军人事务部的其他调查人员一起 威斯康星州麦迪逊退伍军人医疗中心，我们将继续指导有前途的 CDA-2 候选人，并且 从而帮助培养下一代优秀的退伍军人事务部科学家。