NONINVASIVE BIOMARKERS OF PROTEOLYTIC ACTIVITY IN CHILDREN WITH CYSTIC FIBROSIS

囊性纤维化儿童蛋白水解活性的非侵入性生物标志物

• 批准号: 7374362
• 负责人: Scott D SAGEL
• 金额: $ 2.32万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-24 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7374362
• 关键词: bronchiectasis; children; elastin; endopeptidases; genetics; lung; sputum; training; urine

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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, will 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 metalloproteinases types 2 and 9), lung antiproteases (alpha1-antiprotease, secretory leukoprotease inhibitor, tissue inhibitors of metalloproteinases), and elastin breakdown products (desmosine, isodesmosine) in clinical specimens (induced sputum, urine) from CF children, during times of clinical stability, annually over 3 years; 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 as well as biochemically through measurement of elastin breakdown products in sputum and urine), 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); and 3) to examine the influence of genetic modifiers on airway proteolytic activity by determining if protease levels are associated with polymorphisms in genes that are believed to modify CF lung disease (MBL, TNF , TGF- , and A1AT). These results will be crucial to evaluating emerging anti-proteolytic treatments in children with CF. Another objective of this clinical research protocol 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. in the University of Colorado'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.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心机构，不一定为研究者机构。在囊性纤维化（CF）儿童中，蛋白水解活性引起支气管扩张，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）通过定量嗜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），来自CF儿童，在临床稳定期内，每年一次，持续3年; 2）将蛋白水解活性的这些变化与结构性气道损伤相关联（通过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以及通过测量痰和尿中弹性蛋白分解产物的生化指标进行评估），功能性气道损害（通过年度肺功能检测确定）、下气道细菌定植状态和细菌负荷以及相关发病率（住院率、肺部疾病加重率）;和3）通过确定蛋白酶水平是否与基因多态性相关，检查遗传修饰剂对气道蛋白水解活性的影响，据信可改善CF肺病（MBL、TNF、TGF-β和A1 AT）。这些结果将是至关重要的，以评估新兴的抗蛋白水解治疗儿童CF。本临床研究方案的另一个目标是提高和加强Sagel博士的临床研究和以患者为导向的研究方法。Sagel博士将通过完成博士学位接受更正式的培训和教育。在科罗拉多大学的临床科学项目中。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。