Nebulized Nitrite as a Novel Antimicrobial Therapy in Cystic Fibrosis

 描述(由申请人提供)：本申请是由医学博士安娜·泽姆克提交的，题为“雾化亚硝酸盐作为囊性纤维化的一种新型抗菌疗法”，申请的是以患者为导向的研究职业发展奖。泽姆克博士是匹兹堡大学的肺病学家，她需要在人类受试者研究方面接受额外的培训，才能继续她的专业发展，朝着进行转化性肺部研究的长期目标前进，重点是慢性细菌感染。这项建议的短期培训目标是：(1)深入了解进行肺部转译研究；(2)成为肺部细菌感染生物学方面的专家；(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、过敏和重症护理部门进行，该部门在培训内科科学家方面有很强的历史，在培训Zemke博士和进行拟议的翻译研究方面拥有一流的基础设施。这项研究提案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。囊性纤维化是美国高加索人中最常见的致命疾病，以进行性呼吸衰竭和呼吸道感染为特征。铜绿假单胞菌感染高达80%的成人CF，并在肺内高度耐药的生物膜中生长。触发素细菌从生物膜中扩散可能会改善宿主的清除能力，并提高抗生素疗效。亚硝酸钠(AIR001)是一种通过抑制细菌呼吸而具有抗菌活性和分散已建立的生物膜的能力的药剂。当AIR001与氨甲氧基甲酸酯结合时，它对铜绿假单胞菌生物被膜具有额外的活性。AIR001尚未在CF人群中进行测试，但它在肺动脉高压患者中有极好的安全性数据。第一个研究目标包括开发雾化亚硝酸盐和氨甲氧甲酸酯联合治疗成人CF患者铜绿假单胞菌呼吸道感染的概念验证性研究。这一目的验证了亚硝酸盐和氨甲氧基甲酸酯雾化吸入在患有CF的受试者中是安全的假设，并收集了概念验证疗效数据。第二个目标将检验亚硝酸盐在营养复杂的环境中分散生物膜的假设，然后确定亚硝酸盐诱导生物膜分散的机制。(1)正式的人类受试者研究培训；(2)实践的创新研究经验，包括早期的安全方案和进一步的基础科学；(3)经验丰富的多样化指导团队；(4)匹兹堡大学肺、过敏和重症监护科强大的机构环境，将使Zemke博士具备从事肺研究的能力。

 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.