Mentored Patient-Oriented Research Career Development Award

指导以患者为中心的研究职业发展奖

• 批准号: 6784734
• 负责人: Scott D SAGEL
• 金额: $ 13.07万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6784734
• 关键词: Pseudomonas aeruginosa; adolescence (12-20); biomarker; bronchiectasis; clinical research; comorbidity; computed axial tomography; cystic fibrosis; elastin; endopeptidases; enzyme activity; middle childhood (6-11); neutrophil; patient oriented research; proteolysis; respiratory airflow disorder; respiratory airway volume; respiratory function; respiratory infections; sputum; statistics /biometry

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.

描述（由申请人提供）： 在囊性纤维化（CF）儿童中，蛋白水解活性导致支气管扩张，导致进行性肺病和预期寿命显著缩短。 该提案的长期目标之一是确定可预测CF儿童未来临床病程和疾病进展的蛋白水解生物标志物。通过识别那些过度和更具侵略性的蛋白水解活性的儿童，可能会在不可逆的气道损伤发生之前进行抗蛋白水解治疗。 主要假设是，CF儿童具有更明显的蛋白水解活性，如诱导痰中所测量的，将具有更大程度的结构和功能性肺损伤。 将通过以下具体目标检验这一假设：1）通过定量中性粒细胞衍生的蛋白酶的水平来确定蛋白水解活性的变化（弹性蛋白酶，基质金属蛋白酶2型和9型），肺抗蛋白酶（α 1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）（诱导痰、尿液）CF儿童，在临床稳定期间，三年内每年一次;以及2）将蛋白水解活性的这些变化与结构性气道损伤相关联（根据每年高分辨率计算机断层扫描的支气管扩张严重程度和范围进行评估）、功能性气道损害（如通过年度肺功能测试所确定的），下气道细菌定植状态和细菌负荷，和相关发病率（住院率、肺部恶化）。 这些结果将是至关重要的评估新兴的抗蛋白水解治疗儿童CF。 这项申请的另一个目的是提高和加强萨格尔博士的临床调查和以病人为导向的研究方法。 Sagel博士将通过完成博士学位接受更正式的培训和教育。在UC的临床科学计划学位。 他将参加临床流行病学，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，他将积极参与和培训儿科GCRC，并经常与他的赞助商，导师和合作者互动。