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.



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