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.

申请人的总体研究计划集中在LOS和先天免疫的作用上， 系统，并已表明，磷酸化程度的脂质A组分是相关的， LOS诱导先天性免疫性丝氨酸介导的炎症的潜力，一般而言， 奈瑟氏菌病根据这些研究的结果，最近的工作已经开始发展， 潜在的治疗目标淋球菌LOS感染由于N.淋病是导致 每年在美国估计有850，000例，在全世界估计有8700万例。在VA 卫生保健系统，淋病病例在2013年至2017年期间增加，当时的总数 10587期。在美国军队中，服务人员是淋病的高风险群体， 美国预防服务工作队指出，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发病率。一 2007至2015财年，在现役人员中共发现27,658例淋病病例（222.7 每10万名军人中有179.3人死亡，而2018年为每10万名非军人中有179.3人死亡）。目前还没有针对N. 淋病以及由于多药耐药性（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成为一个真实的前景。因此， 需要新的抗淋球菌感染的抗生素。 为此，在建议的资助期内，我们会进行下列项目： 以下：1）LpxC抑制剂和细胞穿透肽;我们最近报道，淋球菌的治疗 与LpxC（催化脂质A生物合成第二步的酶）的抑制剂一起使用， 对于淋球菌的MDR和人类攻击菌株，细胞因子诱导减少，而没有明显的人类 细胞毒性最近，我们评估了一种12个氨基酸的细胞穿透剂的杀菌潜力， 肽（CPP），并发现它穿透细菌膜，对所有多药 测试了淋球菌的耐药菌株和人攻击菌株，并减少了炎性细胞因子诱导， 防止细菌细胞侵入宫颈上皮细胞。这些新数据突出了LpxC抑制剂， CPP是一种很有前途的N.并强烈支持本申请的假设， 用LpxC抑制剂抑制脂质A组分的生物合成并破坏外膜完整性 CPP会影响细菌活力和宿主对N的反应。淋病感染的体外和体内， 将对感染结果产生治疗影响。这两种潜在疗法的转化研究 淋病将是奖励期间拟议调查的主要重点。2)EPTA 抑制剂;我们将继续我们的合作与博士. Charlene Kahler和爱丽丝Vrielink的大学 在西澳大利亚，我们的目标是淋球菌EptA，脂质A的磷酸乙醇胺转移酶， 用小分子抑制剂使N.淋球菌对阳离子抗菌肽的杀灭作用 中性粒细胞和减少炎性细胞因子的诱导。3)淋球菌在中性粒细胞中的存活;我们 我将继续与弗吉尼亚大学的艾莉森·克里斯博士合作，确定视距的影响 结构变异对中性粒细胞中淋球菌存活的影响。4)淋球菌疫苗;与Dr. Peter Beernink的研究，我们将从N.脑膜炎菌株 工程化以表达潜在的保护性N.淋病抗原 总体而言，下一个SRCS资助期的研究将继续支持VA的使命 通过研究促进潜在疗法的转化发展， 疫苗针对淋病，这是由疾病预防控制中心列为紧急公共卫生威胁，由于快速 MDR分离株数量增加。