Nebulized Nitrite as a Novel Antimicrobial Therapy in Cystic Fibrosis

雾化亚硝酸盐作为囊性纤维化的新型抗菌疗法

• 批准号: 10011914
• 负责人: Anna Christine Zemke
• 金额: $ 16.5万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-15 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10011914
• 关键词: Adult; Anaerobic Bacteria; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Antimicrobial Resistance; Bacteria; Bacterial Infections; Bacterial Physiology; Basic Science; Biology; Bronchiectasis; Certification; Chronic; Chronic Obstructive Airway Disease; Clinical Research; Communities; Complex; Critical Care; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Data; Defect; Development; Disease; Doctor of Philosophy; Environment; Epithelial Cells; Ethics; Formulation; Foundations; Genetic Diseases; Goals; Gram-Negative Bacteria; Growth; Human; Human Subject Research; Hypersensitivity; In Vitro; Infection; Infrastructure; Inhalation; Investigation; Lead; Life Style; Lung; Lung diseases; Lung infections; Measurement; Medical; Mentored Patient-Oriented Research Career Development Award; Mentorship; Methemoglobin; Microbial Biofilms; Molecular; Mucociliary Clearance; Nebulizer; Nitrates; Nitrites; Nutritional; Patients; Pharmacologic Substance; Phase; Physicians; Physiological Processes; Pilot Projects; Pneumonia; Polymyxins; Population; Principal Investigator; Proteins; Protocols documentation; Pseudomonas aeruginosa; Pseudomonas aeruginosa infection; Pulmonary Fibrosis; Pulmonary Function Test/Forced Expiratory Volume 1; Pulmonary Hypertension; Recording of previous events; Research; Research Proposals; Research Training; Resistance; Respiration; Respiratory Failure; Respiratory Tract Infections; Respiratory physiology; Safety; Saline; Sampling; Scientist; Sodium; Sodium Nitrite; Spirometry; Sputum; Surface; Techniques; Testing; TimeLine; Training; Translational Research; Universities; Work; airway epithelium; airway surface liquid; antimicrobial; antimicrobial drug; base; career; caucasian American; combat; cystic fibrosis airway epithelia; cystic fibrosis infection; cystic fibrosis patients; drug development; experience; human subject; improved; in vitro activity; in vivo; innovation; insight; metabolic rate; mortality; mucus clearance; mutant; novel; pressure; prevent; programs; public health relevance; safety outcomes; safety testing; screening; translational study

 DESCRIPTION (provided by applicant): This application for a Mentored Patient-Oriented Research Career Development Award is being submitted by Anna Zemke, MD PhD and entitled "Nebulized Nitrite as a Novel Antimicrobial Therapy in Cystic Fibrosis." Dr. Zemke is a pulmonologist at the University of Pittsburgh and requires additional training in human subjects research to continue her professional development toward the long-term goal of conducting translational pulmonary research, with a focus on chronic bacterial infections. The short-term training goals of this proposal are to: (1) Gain an in-depth understanding of conducting pulmonary translational studies, (2) Become an expert in the biology of pulmonary bacterial infections, and (3) Become proficient at techniques used to study bacterial physiology. Integral to the training plan is the Certificate in Clinical Research Program, which includes needed statistical, ethical, and regulatory training. This work will be conducted within the Division of Pulmonary, Allergy, and Critical Care at the University of Pittsburgh, which has a strong history of training physician- scientists and a superb infrastructure for both training Dr. Zemke and conducting the proposed translational research. The central objective of this research proposal is to develop nebulized sodium nitrite as an antimicrobial agent in cystic fibrosis (CF). Cystic fibrosis is the most common lethal disease among Caucasian Americans and is marked by progressive respiratory failure and airway infections. Pseudomonas aeruginosa infects up to 80% of adults with CF, and grows in highly antibiotic resistant biofilms within the lung. Triggerin bacteria to disperse from biofilms may allow for improved clearance by the host and improved antibiotic efficacy. Sodium nitrite (AIR001) is an agent that combines antimicrobial activity, through the suppression of bacterial respiration, with the ability to disperse established biofilms When AIR001 is combined with colistimethate, it has additional activity against P. aeruginosa biofilms. AIR001 has not been tested in the CF population, but it has excellent safety data in pulmonary hypertension patients. The first research aim consists of proof-of-concept studies for developing nebulized nitrite and colistimethate combinations for treating P. aeruginosa airway infections in adults with CF. This aim tests the hypothesis that nebulization of nitrite and colistimethate is safe in subjects with CF and collects proof-of-concept efficacy data. The second aim will test the hypothesis that nitrite disperses biofilms in a nutritionally complex environment and then determine the mechanism of nitrite-induced biofilm dispersal. The combination of (1) formal human subjects research training;(2) hands-on, innovative research experience that includes both early phase safety protocols and further basic science; (3) an experienced, diverse mentorship team; and (4) the strong institutional environment of the Pulmonary, Allergy, and Critical Care Division at the University of Pittsburgh will equip Dr. Zemke for a career in translational pulmonary research.

 描述（由申请人提供）：本申请为指导的患者为导向的研究职业发展奖是由安娜Zemke，医学博士和博士提交的，题为“雾化亚硝酸盐作为一种新型的抗微生物治疗囊性纤维化。Zemke博士是匹兹堡大学的肺病学家，需要在人类受试者研究方面接受额外的培训，以继续她的专业发展，实现进行转化性肺部研究的长期目标，重点是慢性细菌感染。本提案的短期培训目标是：（1）深入了解进行肺部转化研究，（2）成为肺部细菌感染生物学专家，（3）精通用于研究细菌生理学的技术。培训计划的组成部分是临床研究计划证书，其中包括所需的统计，伦理和监管培训。这项工作将在匹兹堡大学的肺部，过敏和重症监护部门进行，该部门在培训医生科学家方面有着悠久的历史，并且在培训Zemke博士和进行拟议的转化研究方面拥有一流的基础设施。这项研究的主要目的是开发雾化亚硝酸钠作为囊性纤维化（CF）的抗菌剂。囊性纤维化是美国白人中最常见的致死性疾病，其特征是进行性呼吸衰竭和气道感染。铜绿假单胞菌感染高达80%的CF成人，并在肺内的高度抗生素耐药性生物膜中生长。触发细菌从生物膜分散可以允许宿主的改善的清除和改善的抗生素功效。亚硝酸钠（AIR 001）是一种通过抑制细菌呼吸而具有抗菌活性的试剂，具有分散已建立的生物膜的能力。当AIR 001与多粘菌素E甲磺酸盐组合时，它对铜绿假单胞菌生物膜具有额外的活性。AIR 001尚未在CF人群中进行测试，但它在肺动脉高压患者中具有良好的安全性数据。第一个研究目标包括开发雾化亚硝酸盐和多粘菌素E甲磺酸盐组合用于治疗CF成人铜绿假单胞菌气道感染的概念验证研究。该目的是检验亚硝酸盐和多粘菌素E甲磺酸盐雾化吸入在CF受试者中安全的假设，并收集概念验证有效性数据。第二个目标将测试的假设，亚硝酸盐分散在营养复杂的环境中的生物膜，然后确定亚硝酸盐诱导的生物膜分散的机制。结合（1）正式的人类受试者研究培训;（2）动手，创新的研究经验，包括早期阶段的安全协议和进一步的基础科学;（3）经验丰富，多样化的导师团队;和（4）匹兹堡大学肺部，过敏和重症监护部门的强大机构环境将使Zemke博士能够从事转化肺部研究。

项目成果

Olfaction before and after initiation of elexacaftor-tezacaftor-ivacaftor in a cystic fibrosis cohort.

• DOI: 10.1002/alr.22891
• 发表时间: 2022-03
• 期刊: International forum of allergy & rhinology
• 影响因子: 6.4
• 作者: Bacon DR;Stapleton A;Goralski JL;Ebert CS Jr;Thorp BD;Nouraie M;Shaffer AD;Senior BA;Lee SE;Zemke AC;Kimple AJ
• 通讯作者: Kimple AJ

Bacterial respiratory inhibition triggers dispersal of Pseudomonas aeruginosa biofilms.

• DOI: 10.1128/aem.01101-23
• 发表时间: 2023-10-31
• 期刊: Applied and environmental microbiology
• 影响因子: 4.4

Elexacaftor-Tezacaftor- Ivacaftor improves sinonasal outcomes in cystic fibrosis.

• DOI: 10.1016/j.jcf.2022.03.002
• 发表时间: 2022-09
• 期刊: JOURNAL OF CYSTIC FIBROSIS
• 影响因子: 5.2
• 作者: Stapleton, Amanda L.;Kimple, Adam J.;Goralski, Jennifer L.;Nouraie, S. Mehdi;Branstetter, Barton F.;Shaffer, Amber;Pilewski, Joseph M.;Senior, Brent A.;Lee, Stella E.;Zemke, Anna C.
• 通讯作者: Zemke, Anna C.

Right on the Nose: IL-17C and Nasal Host Defense.

就在鼻子上：IL-17C 和鼻宿主防御。

• DOI: 10.1165/rcmb.2019-0236ed
• 发表时间: 2020
• 期刊: American journal of respiratory cell and molecular biology
• 影响因子: 6.4
• 作者: Zemke,AnnaC;Robinson,KevenM
• 通讯作者: Robinson,KevenM

Elexacaftor-tezacaftor-ivacaftor decreases pseudomonas abundance in the sinonasal microbiome in cystic fibrosis.

Elexacaftor-tezacaftor-ivacaftor 降低囊性纤维化鼻窦微生物组中假单胞菌的丰度。

• DOI: 10.1002/alr.23288
• 发表时间: 2024
• 期刊: International forum of allergy & rhinology
• 影响因子: 6.4
• 作者: Zemke,AnnaC;Hilliam,Yasmin;Stapleton,AmandaL;Kimple,AdamJ;Goralski,JenniferL;Shaffer,AmberD;Pilewski,JosephM;Senior,BrentA;Lee,StellaE;Cooper,VaughnS
• 通讯作者: Cooper,VaughnS