Mentored Patient-Oriented Research Career Development Award

描述（由申请人提供）： 在患有囊性纤维化 (CF) 的儿童中，蛋白水解活性会导致支气管扩张，导致进行性肺部疾病并显着缩短预期寿命。 该提案的长期目标之一是定义可预测 CF 儿童未来临床病程和疾病进展的蛋白水解生物标志物。通过识别那些具有过度和更具侵略性的蛋白水解活性的儿童，有可能在发生不可逆的气道损伤之前进行抗蛋白水解治疗的干预。 主要假设是，根据诱导痰检测结果，具有更明显蛋白水解活性的 CF 儿童会出现更大程度的结构和功能性肺损伤。 该假设将通过以下具体目标进行检验：1) 通过定量临床标本中中性粒细胞来源的蛋白酶（弹性蛋白酶、基质金属蛋白酶 2 型和 9 型）、肺抗蛋白酶（α1 抗蛋白酶、分泌性白细胞蛋白酶抑制剂、金属蛋白酶组织抑制剂）和弹性蛋白分解产物（锁链素、异锁链素）的水平来确定蛋白水解活性的变化（诱导三年内每年在临床稳定期间收集 CF 儿童的痰液、尿液； 2) 将蛋白水解活性的这些变化与结构性气道损伤（通过每年高分辨率计算机断层扫描评估支气管扩张的严重程度和范围进行评估）、功能性气道损伤（通过每年肺功能测试确定）、下气道细菌定植状态和细菌负荷以及相关发病率（住院率、肺部恶化率）联系起来。 这些结果对于评估 CF 儿童的新兴抗蛋白水解疗法至关重要。 此应用程序的另一个目标是增强和加强 Sagel 博士的临床调查和以患者为导向的研究方法。 萨格尔博士将在完成博士学位后接受更正式的培训和教育。加州大学临床科学项目学位。 他将学习临床流行病学、生物伦理学、临床试验设计、药代动力学和人类遗传学课程，并完成一篇关于 CF 蛋白水解活性的论文。此外，他还将积极参与儿科 GCRC 的培训，并经常与他的资助者、导师和合作者互动。

DESCRIPTION (provided by applicant): In children with cystic fibrosis (CF) proteolytic activity causes bronchiectasis, resulting in progressive lung disease and marked shortening of life expectancy. One of the long-term objectives for this proposal is to define proteolytic biomarkers that are predictive of future clinical course and disease progression in children with CF. By identifying those children with excessive and more aggressive proteolytic activity, it may be possible to intervene with anti-proteolytic treatments before irreversible airway damage occurs. The main hypothesis is that CF children with more pronounced proteolytic activity, as measured in induced sputum, would have a greater degree of structural and functional lung damage. This hypothesis will be tested through the following specific aims: 1) to determine changes in proteolytic activity by quantitating levels of neutrophil derived proteases (elastase, matrix metalloproteinase Types 2 and 9), lung antiproteases (alpha1antiprotease, secretory leukoprotease inhibitor, tissue inhibitors of metalloproteinase), and elastin breakdown products (desmosine, isodesmosine) in clinical specimens (induced sputum, urine) from CF children, during times of clinical stability, annually over three years; and 2) to correlate these changes in proteolytic activity with structural airway damage (assessed by severity and extent of bronchiectasis on annual high resolution computed tomography scans), functional airway impairment (as determined by annual pulmonary function testing), lower airway bacterial colonization status and bacterial burden, and related morbidities (rates of hospitalization, pulmonary exacerbations). These results will be crucial to evaluating emerging antiproteolytic treatments in children with CF. Another objective of this application is to enhance and strengthen Dr. Sagel's approach to clinical investigation and patient-oriented research. Dr. Sagel will receive more formal training and education by completing his Ph.D. degree in the UC's Clinical Science Program. He will take courses in clinical epidemiology, bioethics, clinical trial design, pharmacokinetics, and human genetics, and complete a thesis about proteolytic activity in CF. In addition, he will actively participate and train in the Pediatric GCRC, and frequently interact with his sponsor, mentors, and collaborators.