BLRD Research Career Scientist Award Application

BLRD 研究职业科学家奖申请

• 批准号: 10360383
• 负责人: Gary A Jarvis
• 金额: --
• 依托单位: VETERANS AFFAIRS MED CTR SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-10-01 至 2026-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10360383
• 关键词: Advisory Committees; Afghanistan; Amino Acids; Anabolism; Antibiotics; Antigens; Antimicrobial Cationic Peptides; Award; California; Cardiovascular system; Cells; Centers for Disease Control and Prevention (U.S.); Cervical; Collaborations; Communicable Diseases; Community Participation; Data; Development; Disease; Drug Kinetics; Education; Engineering; Environment; Enzymes; Epithelial Cells; Faculty; Family; Female; Funding; Funding Agency; Gonorrhea; Growth; Healthcare; Healthcare Systems; Human; Human Resources; Immune; Immune response; In Vitro; Incidence; Infection; Inflammation; Inflammatory; Innate Immune System; International; Investigation; Iraq; Journals; Lead; Lipid A; Measurable; Mediating; Membrane; Mentors; Military Personnel; Mission; Modeling; Morbidity - disease rate; Multi-Drug Resistance; Neisseria; Neisseria gonorrhoeae; Neisseria meningitidis; Outcome; Patient Care; Peer Review; Peptides; Phosphorylation; Positive Test Result; Postdoctoral Fellow; Preventive service; Public Health; Reporting; Research; Research Personnel; Risk Behaviors; Role; San Francisco; Scientist; Services; Severities; Sexually Transmitted Diseases; Students; Surveys; Testing; Therapeutic; Time; Toxic effect; Transferase; Universities; Vaccines; Variant; Vesicle; Veterans; Virginia; Virulence; Western Australia; Woman; Work; active duty; antimicrobial; bactericide; base; career; cytokine; cytotoxicity; design; high risk; high risk population; in vivo; in vivo evaluation; inhibitor; lipid biosynthesis; male; men; military service; military veteran; mouse model; neutrophil; novel; novel therapeutics; patient population; phosphoethanolamine; prevent; programs; reproductive tract; resistant strain; service member; small molecule inhibitor; symposium; therapeutic target; translational study

The overall research program of the applicant has focused on the role of LOS and the innate immune system and has shown that the degree of phosphorylation of the lipid A component is correlated with the potential of the LOS to induce innate immune cytokine-mediated inflammation and, in general, with the severity of Neisserial disease. Based on the results of these studies, recent work has undertaken the development of potential therapeutics targeting gonococcal LOS as infections due to N. gonorrhoeae are a major cause of morbidity with an estimated 850,000 cases in the U.S. and 87 million cases worldwide annually. Within the VA Health Care System, cases of gonorrhea increased between 2013 and 2017 with the total number in that time period at 10,587. Within the U.S. military, service members are a defined high-risk group for gonorrhea as noted by the U.S. Preventive Services Task Force as the high-risk environment of active military service is thought to increase risky behavior and, thus, the rate of sexually transmitted infections including gonorrhea. A total of 27,658 cases of gonorrhea were identified among active duty personnel during FY 2007 to 2015 (222.7 per 100,000 military compared with 179.3 per 100,000 non-military in 2018). There is no vaccine to N. gonorrhoeae and a great need for new antibiotics due to the alarming rise in multidrug-resistance (MDR), which is making emergence of untreatable gonococcal infections a real prospect. Thus, there is a compelling need for new antimicrobials for gonococcal infections. To this end, the projects to be pursued during the proposed funding period of this SRCS award are as follows: 1) LpxC inhibitors and cell-penetrating peptides; we recently reported that treatment of gonococci with an inhibitor of LpxC, the enzyme that catalyzes the second step of lipid A biosynthesis, was bactericidal for MDR and human challenge strains of gonococci and reduced cytokine induction without apparent human cell cytotoxicity. Most recently, we evaluated the bactericidal potential of a 12 amino acid cell-penetrating peptide (CPP) and found that it penetrated the bacterial membrane and was bactericidal for all multi-drug resistant and human challenge strains of gonococci tested and reduced inflammatory cytokine induction and prevented bacterial cell invasion of cervical epithelial cells. These novel data highlight LpxC inhibitors and CPP as promising antimicrobials for N. gonorrhoeae and strongly support the hypothesis of this application that inhibiting the biosynthesis of lipid A components with LpxC inhibitors and disrupting outer membrane integrity with CPP will impact bacterial viability and host response to N. gonorrhoeae infection in vitro and in vivo, which will have a therapeutic impact on infection outcomes. Translational studies of these two potential therapeutics for gonorrhea will be the primary focus of the investigations proposed for the award period. 2) EptA inhibitors; we will continue our collaboration with Drs. Charlene Kahler and Alice Vrielink of the University of Western Australia in which we are targeting gonococcal EptA, the phosphoethanolamine transferase for lipid A, with small molecule inhibitors to sensitize N. gonorrhoeae to killing by cationic antimicrobial peptides inside neutrophils and reduce the induction of inflammatory cytokines. 3) Gonococcal survival in neutrophils; we will continue our collaboration with Dr. Alison Criss of the University of Virginia to determine the impact of LOS structural variation on the survival of gonococci in PMNs. 4) Gonococcal vaccine; in collaboration with Dr. Peter Beernink of UCSF, we will develop native outer membrane vesicle vaccines from N. meningitidis strains engineered to express potentially protective N. gonorrhoeae antigens. Overall, the research proposed for the next SRCS funding period will continue to support the mission of VA Healthcare through studies that will facilitate the translational development of potential therapeutics and vaccines targeting gonorrhea, which is classified by CDC as an urgent public health threat due to the rapid increase in the number of MDR isolates.

申请者的整体研究计划集中在LOS和先天免疫的作用上。 系统，并已表明，磷脂A组分的磷酸化程度与 LOS诱导先天免疫细胞因子介导的炎症的可能性，通常情况下，与严重的 尼斯利氏病的症状。根据这些研究的结果，最近的工作开展了以下工作 针对淋球菌LOS的潜在治疗方法是由淋球菌引起的感染，是 美国的发病率估计为85万例，全球每年有8700万例。在退伍军人事务部内 在卫生保健系统中，2013至2017年间淋病病例有所增加，同期淋病病例总数 期内报10,587点。在美国军队中，服役人员是淋病的高危人群，因为 美国预防服务工作组指出，现役军人的高风险环境是 被认为会增加危险行为，从而增加包括淋病在内的性传播感染的比率。一个 在2007财年至2015年期间，现役人员中共发现27,658例淋病(222.7 每100,000名军人中有179.3人，而2018年每100,000名非军人中有179.3人)。目前还没有针对N。 淋病和由于多重耐药(MDR)的惊人上升而对新抗生素的巨大需求， 这使得无法治愈的淋球菌感染的出现成为现实。因此，有一个令人信服的 需要新的抗菌剂来治疗淋球菌感染。 为达到这个目的，在这项奖励计划的拟议资助期内进行的项目如下 1)LpxC抑制剂和细胞穿透肽；我们最近报道了淋球菌的治疗 在LpxC抑制剂的作用下，催化第二步脂质A生物合成的酶具有杀菌作用 对于MDR和人类挑战淋球菌菌株和减少细胞因子诱导而没有明显的人 细胞毒性。最近，我们评估了一种12个氨基酸的穿透细胞的杀菌潜力。 多肽(CPP)，发现它能穿透细菌膜，对多种药物都有杀菌作用 对淋球菌耐药株和人类挑战株进行测试并减少炎性细胞因子的诱导和 防止细菌侵袭宫颈上皮细胞。这些新数据突出了LpxC抑制剂和 CPP是很有前途的淋球菌抗菌剂，并有力地支持了这一应用的假设 LpxC抑制剂抑制脂质A组分的生物合成并破坏外膜完整性 在体外和体内，CPP会影响细菌活力和宿主对淋球菌感染的反应，这 将对感染结果产生治疗影响。这两种潜在疗法的翻译研究 对于淋病，将是建议在颁奖期间进行的调查的主要重点。2)EPTA 我们将继续与加州大学的Charlene Kahler博士和Alice Vrielink博士合作 在西澳大利亚州，我们的目标是淋球菌EPTA，A类的磷酸乙醇胺转移酶， 使用小分子抑制剂使淋球菌对体内阳离子抗菌肽的杀灭敏感 减少中性粒细胞和炎性细胞因子的诱导。3)淋球菌在中性粒细胞中的存活； 将继续与弗吉尼亚大学的艾莉森·克里斯博士合作，以确定洛杉矶的影响 淋球菌在中性粒细胞中存活的结构变异。4)淋球菌疫苗； 加州大学旧金山分校的Peter Beernink说，我们将从脑膜炎奈瑟菌菌株开发天然的外膜囊泡疫苗 经改造后可表达具有潜在保护性的淋病奈瑟菌抗原。 总体而言，下一个SRCS供资期间拟议的研究将继续支持退伍军人事务部的任务 通过研究促进潜在疗法的翻译开发和医疗保健 针对淋病的疫苗，淋病被疾控中心列为紧急公共卫生威胁，因为 耐多药菌株数量增加。