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）：这份以患者为导向的研究职业发展奖的申请由医学博士安娜·泽姆克（Anna Zemke）提交，题为“雾化亚硝酸盐作为囊性纤维化的新型抗菌疗法”。泽姆克博士是一名肺病学家。她在匹兹堡大学获得博士学位，并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，以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) 精通所用技术研究细菌生理学的一部分是临床研究证书计划，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科、过敏和重症监护部门进行。 ，拥有悠久的培训历史该研究计划的中心目标是开发雾化亚硝酸钠作为囊性纤维化 (CF) 的抗菌剂。这是一种美国白人的致命疾病，其特征是高度进行性呼吸衰竭和气道感染，高达 80% 的成人患有 CF，并在抗生素中生长。触发素细菌从生物膜中分散，可以提高宿主的清除率并提高抗生素功效，亚硝酸钠 (AIR001) 是一种通过抑制细菌呼吸来结合抗菌活性和分散能力的药物。已建立的生物膜 当 AIR001 与甲粘菌酯结合使用时，它具有针对铜绿假单胞菌生物膜的额外活性，但 AIR001 尚未在 CF 中进行测试。人群，但它在肺动脉高压患者中拥有出色的安全性数据。第一个研究目标包括开发雾化亚硝酸盐和粘菌酯组合用于治疗成人 CF 铜绿假单胞菌气道感染的概念验证研究。亚硝酸盐和粘菌素雾化剂对于 CF 受试者是安全的，并收集概念验证功效数据。第二个目标将检验亚硝酸盐在生物膜中分散的假设。营养复杂的环境，然后确定亚硝酸盐引起的生物膜扩散的机制（1）正式的人体研究培训；（2）实践、创新的研究经验，包括早期安全方案和进一步的基础科学； ) 经验丰富、多元化的导师团队；(4) 匹兹堡大学肺部、过敏和重症监护部门强大的机构环境将为 Zemke 博士从事转化性肺部研究奠定基础。

项目成果

Dispersal of Epithelium-Associated Pseudomonas aeruginosa Biofilms.

上皮相关的铜绿假单胞菌生物膜的分散。

• 发表时间: 2020
• 影响因子: 4.8
• 作者: Zemke, Anna C;D'Amico, Emily J;Snell, Emily C;Torres, Angela M;Kasturiarachi, Naomi;Bomberger, Jennifer M
• 通讯作者: Bomberger, Jennifer M

NADH Dehydrogenases in Pseudomonas aeruginosa Growth and Virulence.

铜绿假单胞菌生长和毒力中的 NADH 脱氢酶。

• 发表时间: 2019
• 作者: Torres, Angela;Kasturiarachi, Naomi;DuPont, Matthew;Cooper, Vaughn S;Bomberger, Jennifer;Zemke, Anna
• 通讯作者: Zemke, Anna

Sodium Nitrite Inhibits Killing of Pseudomonas aeruginosa Biofilms by Ciprofloxacin.

亚硝酸钠抑制环丙沙星对铜绿假单胞菌生物膜的杀灭。

• 发表时间: 2017-01
• 影响因子: 4.9
• 作者: Zemke, Anna C;Kocak, Brian R;Bomberger, Jennifer M
• 通讯作者: Bomberger, Jennifer M

Clinical predictors of cystic fibrosis chronic rhinosinusitis severity.

囊性纤维化慢性鼻窦炎严重程度的临床预测因素。

• 发表时间: 2019
• 作者: Zemke, Anna C;Nouraie, Seyed Mehdi;Moore, John;Gaston, Jordan R;Rowan, Nicholas R;Pilewski, Joseph M;Bomberger, Jennifer M;Lee, Stella E
• 通讯作者: Lee, Stella E

Bacterial respiratory inhibition triggers dispersal of Pseudomonas aeruginosa biofilms.

细菌呼吸抑制引发铜绿假单胞菌生物膜的扩散。

• 发表时间: 2023-10-31
• 影响因子: 4.4
• 作者: Zemke, Anna C;D'Amico, Emily J;Torres, Angela M;Carreno;Keeley, Patrick;DuPont, Matt;Kasturiarachi, Naomi;Bomberger, Jennifer M
• 通讯作者: Bomberger, Jennifer M