BLRD Research Career Scientist Award Application

BLRD 研究职业科学家奖申请

• 批准号: 10512756
• 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/10512756
• 关键词: Afghanistan; Amino Acids; Anabolism; Antibiotics; Antigens; Antimicrobial Cationic Peptides; Award; California; Cardiovascular system; Cells; Cervical; Classification; 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; Invaded; 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; Penetration; Peptides; Phosphorylation; Positive Test Result; Postdoctoral Fellow; 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; Translation Initiation; United States Preventative Services Task Force; Universities; Vaccines; Variant; Vesicle; Veterans; Virginia; Virulence; Western Australia; Woman; Work; active duty; antimicrobial; bactericide; career; cytokine; cytotoxicity; design; high risk; high risk population; in vivo; in vivo evaluation; inhibitor; lipid biosynthesis; male; men; military service; 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.

申请人的整体研究计划集中于LOS和先天免疫的作用 系统并表明脂质A成分的磷酸化程度与 LOS诱导先天免疫细胞因子介导的炎症的潜力，通常 奈瑟氏病。根据这些研究的结果，最近的工作已经进行了 靶向淋球菌LO的潜在疗法作为淋病链球菌引起的感染是导致的主要原因 美国发病率估计为美国850,000例，全球8700万例病例。在VA内 医疗保健系统，2013年至2017年之间的淋病病例增加，当时总数 时间为10,587。在美国军方中，服务成员是淋病的定义高风险团体 美国预防服务工作队指定为活跃兵役的高风险环境是 被认为会增加风险行为，从而增加了包括淋病在内的性传播感染率。一个 在2007年至2015年期间，在现役人员之间总共确定了27,658例淋病病例（222.7 每100,000名军队，而2018年每100,000名非军事人数为179.3）。没有疫苗到N。 淋病，并且由于多种耐药性（MDR）的震惊，对新抗生素的急需 这使得不可治疗的淋球菌感染成为真正的前景。因此，有一个引人入胜的 需要用于淋球菌感染的新抗菌剂。 为此，在本SRCS奖的拟议资助期间要进行的项目是 以下内容：1）LPXC抑制剂和细胞穿透肽；我们最近报道了淋球菌的治疗 使用LPXC的抑制剂，催化脂质A生物合成的第二步的酶为杀菌 对于MDR和人类的淋加球挑战菌株和降低的细胞因子诱导而没有明显的人类 细胞细胞毒性。最近，我们评估了12个氨基酸细胞渗透的杀菌电位 肽（CPP），发现它渗透了细菌膜，并且对所有多药物均为杀菌性 淋球菌的抗性和人类挑战菌株测试并减少了炎症性细胞因子诱导和 防止细菌细胞侵袭宫颈上皮细胞。这些新的数据突出了LPXC抑制剂和 CPP是淋病猪笼草的有希望的抗菌剂，并强烈支持该应用的假设 抑制具有LPXC抑制剂的脂质A成分的生物合成并破坏外膜完整性 使用CPP会影响细菌的生存能力，并在体外和体内影响淋病感染猪笼草。 将对感染结果产生治疗影响。这两种潜在疗法的翻译研究 因为淋病将是颁奖期提议的调查的主要重点。 2）EPTA 抑制剂；我们将继续与Drs合作。大学的夏琳·卡勒（Charlene Kahler）和爱丽丝·弗里琳克（Alice Vrielink） 西澳大利亚州靶向淋球菌EPTA，脂质乙醇胺转移酶用于脂质A， 用小的分子抑制剂使淋病链球菌敏感以通过阳离子抗菌肽杀死 中性粒细胞并减少炎症细胞因子的诱导。 3）中性粒细胞中的淋球菌存活；我们 将继续我们与弗吉尼亚大学的艾莉森·克里斯（Alison Criss）博士确定LOS的影响 PMN中淋球菌存活的结构变化。 4）淋球菌疫苗；与博士合作 UCSF的彼得·贝宁克（Peter Beernink 设计为表达潜在的保护性淋病抗原。 总体而言，下一个SRCS资金期间提出的研究将继续支持VA的使命 通过研究将促进潜在治疗剂的转化发展和 靶向淋病的疫苗，该疫苗被疾病预防控制中心归类为紧急的公共卫生威胁 MDR分离株的数量增加。