Use of Phosphodiesterase Inhibitors to Evaluate the Pathobiology of CF

描述（由申请人提供）：Taylor-Mesar博士致力于发展临床和转化研究的学术生涯，有助于理解囊性纤维化（CF）肺病的病理生理学和治疗。她在医学院之前就开始参与研究，并在整个培训期间一直持续下去。她发表了手稿，并获得了在医学院，住院医生和奖学金期间进行的项目的资金。此外，她在奖学金项目期间展示了将来自多个机构和实验室的科学家联系起来的卓越能力。在她担任她的第一个教师职位后的短时间内，泰勒博士利用CF基金会的资金和培训，在新墨西哥州大学（UNM）建立CF临床研究计划的基础设施。与此同时，她制定了她的检察官发起的协议，为此她收到了内部和外部的资金。作为国家犹太人健康（NJH）的教师，泰勒-萨拉尔博士将受益于现有的科学合作的财富。她将获得NJH和儿童医院肺部医学领域领导者的指导，并且她将获得CF计划以及通过科罗拉多临床和转化科学研究所提供的完善的临床和转化研究基础设施。她的导师和该机构致力于提供时间和支持，泰勒博士将需要发挥她的特殊潜力，成为一名独立的临床研究者。尽管Taylor-Mendar博士通过在CF治疗开发网络的活动获得了一些试验监督经验，但她确定了对她的职业发展至关重要的具体培训需求;这些包括用于评估CF临床研究关键生物标志物的实验室技术培训，通过统计方法和分析以及药理学方面的正规培训，发展临床试验设计方面的专业知识，建立一个指导小组，以获得具有临床试验设计和实施经验的高级研究人员的指导，并提高成为一名富有成效、独立的学术临床科学家所需的基本科学和管理技能。她的计划，以满足这些培训需求已在她的职业发展计划中详细说明，并将包括通过临床研究计划硕士课程，在实验室动手培训，并指导。Taylor-Mesar博士的研究项目将侧重于使用特定的药物类别来探索CF肺病病理生物学的核心方面。拟定的治疗干预将解决导致CF发病率和死亡率的病理学的两个关键因素：1）钠过度吸收和缺乏氯化物分泌导致的气道表面脱水，以及2）慢性肺部感染和炎症导致的气道损伤。先前发表的CF细胞系研究表明，通过增加cGMP和恢复ENaC的抑制作用，可通过给予磷酸二酯酶抑制剂（PDEi）（如西地那非）逆转钠的过度吸收。5使用西地那非恢复ENaC抑制作用可使细胞器过度酸化及其下游效应（包括糖基化紊乱）正常化。6 -7此外，在CF细胞系和动物模型中已经显示，PDE 1/类似物可以增强氯化物分泌和/或校正F508 del CFTR的表面定位。8 -9最后，临床证据表明，在患有严重CF肺病和肺血管疾病的患者中，使用西地那非治疗后，运动耐量的主观和客观测量值都有可能得到改善。10本项目的目标是将本研究的结果转化为使用FDA批准的口服疗法治疗CF患者的临床试验。本项目的具体目的是：1）确定CF受试者全身给予PDEi的安全性和耐受性; 2）证明CF患者全身给予PDEi的药代动力学等同于无CF患者; 3）通过测量治疗前后的结局，确定CF肺病患者全身给予PDEi的机制。这些初步研究的结果将有助于确定西地那非治疗CF肺病的安全性、药代动力学和作用机制。Taylor-Mesar博士将使用本申请中描述的试点研究的数据以及她在本奖项期间开发的技能和知识基础，设计一项大型多中心试验，以确定全身性PDEi给药是否会改善CF肺病的肺功能、加重频率和运动耐量。

DESCRIPTION (provided by applicant): Dr. Taylor-Cousar is committed to developing an academic career in clinical and translational research that contributes to the understanding of the pathophysiology and treatment of Cystic Fibrosis (CF) lung disease. Her involvement in research began prior to medical school, and has continued throughout her training. She has published manuscripts and obtained funding for projects performed during medical school, residency and fellowship. Additionally, she demonstrated an exceptional ability to bridge scientists from multiple institutions and laboratories during her fellowship project. In a short period of time after she assumed her first faculty position, Dr. Taylor-Cousar utilized funding and training from the CF Foundation to establish the infrastructure for a CF clinical research program at the University of New Mexico (UNM). At the same time, she developed her investigator-initiated protocols, for which she received internal and external funding. As faculty at National Jewish Health (NJH), Dr. Taylor-Cousar will benefit from the wealth of scientific collaborations that are available. She will receive mentorship from leaders in the field of pulmonary medicine both at NJH and Children's Hospital, and she will have access to the well-established infrastructure for clinical and translational research that is available within the CF program as well as through the Colorado Clinical and Translational Science Institute. Her mentors and the institution are committed to providing the time and support that Dr. Taylor-Cousar will need to fulfill her exceptional potential to become an independent clinical investigator. Although Dr. Taylor-Cousar gained some experience in trial oversight through her activities in the CF Therapeutics Development Network, she has identified specific training needs that will be essential for her to develop her career; these include training in laboratory techniques used to evaluate biomarkers critical to the conduct of CF clinical research, development of expertise in the design of clinical trials through formal training in statistical methods and analysis and pharmacology, establishment of a mentoring team to obtain guidance from senior investigators with experience in the design and conduct of clinical trials, and refinement of the fundamental scientific and administrative skills necessary to become a productive, independent academic clinical scientist. Her plans for fulfilling these training needs have been detailed in her career development plan and will include coursework through the Masters in Clinical Research Program, hands-on training in the laboratory, and mentorship. Dr. Taylor-Cousar's research project will focus on using a specific drug class to explore central aspects of the pathobiology of CF lung disease. The proposed therapeutic intervention will address two factors critical to the pathology that leads to the morbidity and mortality from CF: 1) Dehydrated airway surfaces resulting from sodium hyperabsorption and lack of chloride secretion, and 2) Airway damage caused by chronic lung infection and inflammation. Previously published work in CF cell lines has demonstrated that by increasing cGMP and restoring inhibition of ENaC, sodium hyperabsorption may be reversed by administration of a phosphodiesterase inhibitor (PDEi), such as sildenafil.5 Using sildenafil to restore ENaC inhibition results in normalization of organellar hyperacidification and its downstream effects, including disordered glycosylation, predisposition to adherence by Pseudomonas aeruginosa and consequent inflammation.6-7 Additionally, it has been shown in CF cell lines and animal models, that PDEi/analogues can enhance chloride secretion and/or correct surface localization of F508del CFTR.8-9 Finally, clinical evidence suggests the potential for improvement in both subjective and objective measurements of exercise tolerance in patients with severe CF lung disease and pulmonary vascular disease who are treated with sildenafil.10 The goal of this project is to translate the results from this body of work into clinical trials in patients with CF using an FDA-approved oral therapy. The Specific Aims of this project are to: 1) Establish safety and tolerability of systemic PDEi administration to subjects with CF 2) Demonstrate that pharmacokinetics of systemic PDEi administration in patients with CF are equivalent to those without CF and 3) Establish the mechanism(s) for use of systemic PDEi administration in CF lung disease by measuring outcomes before and after therapy. The results of these pilot studies will aid in establishing safety, pharmacokinetics and mechanism of action of sildenafil in the treatment of CF lung disease. Dr. Taylor-Cousar will use data from the pilot studies described in this application, and the skills and knowledge base she develops during the period of this award, to design a large, multi-center trial to determine if systemic PDEi administration will improve lung function, frequency of exacerbations and exercise tolerance in CF lung disease