Use of Phosphodiesterase Inhibitors to Evaluate the Pathobiology of CF

描述（由申请人提供）：Taylor-Cousar博士致力于在临床和转化研究方面发展学术生涯，有助于理解囊性纤维化（CF）肺部疾病的病理生理学和治疗。她在医学院之前就开始参与研究，并在整个培训过程中一直持续。她在医学院、住院医师和研究员期间发表了手稿并获得了项目资助。此外，在她的奖学金项目中，她表现出了连接来自多个机构和实验室的科学家的非凡能力。在她担任第一个教职后的很短时间内，Taylor-Cousar博士利用CF基金会的资金和培训，在新墨西哥大学（UNM）建立了CF临床研究项目的基础设施。与此同时，她制定了她的调查员发起的协议，为此她得到了内部和外部的资助。作为国家犹太人健康中心（NJH）的教员，Taylor-Cousar博士将受益于现有的丰富的科学合作。她将接受NJH和儿童医院肺部医学领域领导者的指导，她将可以使用CF项目以及科罗拉多州临床和转化科学研究所建立的临床和转化研究基础设施。她的导师和该机构致力于为Taylor-Cousar博士提供时间和支持，以实现她成为一名独立临床研究者的非凡潜力。虽然Taylor-Cousar博士通过她在CF治疗发展网络的活动获得了一些试验监督经验，但她已经确定了对她的职业发展至关重要的特定培训需求；这些培训包括用于评估对CF临床研究至关重要的生物标志物的实验室技术培训，通过统计方法、分析和药理学方面的正式培训，开发临床试验设计方面的专业知识，建立一个指导团队，从具有临床试验设计和实施经验的高级研究人员那里获得指导。完善基本的科学和管理技能，成为一个富有成效的，独立的学术临床科学家。她为满足这些培训需求的计划已经在她的职业发展计划中详细列出，包括临床研究硕士课程、实验室实践培训和指导。Taylor-Cousar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。建议的治疗干预将解决导致CF发病率和死亡率的两个关键病理因素：1)钠过度吸收和氯分泌缺乏导致气道表面脱水，2)慢性肺部感染和炎症引起的气道损伤。先前发表的CF细胞系的研究表明，通过增加cGMP和恢复ENaC的抑制，钠的高吸收可以通过给药磷酸二酯酶抑制剂（PDEi），如西地那非来逆转使用西地那非恢复ENaC抑制可导致细胞器高酸化的正常化及其下游效应，包括糖基化紊乱、铜绿假单胞菌粘附的易感以及随之而来的炎症。此外，在CF细胞系和动物模型中已经显示，PDEi/类似物可以增强氯化物分泌和/或纠正F508del cftr的表面定位。最后，临床证据表明，在接受西地那非治疗的严重CF肺部疾病和肺血管疾病患者的主观和客观运动耐量测量中，PDEi/类似物都有改善的潜力该项目的目标是将这项工作的结果转化为使用fda批准的口服治疗的CF患者的临床试验。该项目的具体目的是：1)建立CF患者全身给药PDEi的安全性和耐受性2)证明CF患者全身给药PDEi的药代动力学与非CF患者相当3)通过测量治疗前后的结果，建立CF肺部疾病全身给药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-Cousar博士将使用本申请中描述的试点研究的数据，以及她在获奖期间发展的技能和知识基础，设计一项大型多中心试验，以确定系统性PDEi给药是否会改善CF肺病的肺功能、恶化频率和运动耐受性

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