Genetic Determinants: Elastin Quality and Quantity

遗传决定因素：弹性蛋白的质量和数量

• 批准号: 7231246
• 负责人: ROBERT P. MECHAM
• 金额: $ 42.46万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7231246
• 关键词: Affect; Alveolar; Animal Model; Apoptosis; Bronchiectasis; Cells; Characteristics; Chronic Obstructive Airway Disease; Cigarette smoke-induced emphysema; Clinical; Cutis Laxa; DNA; Data; Defect; Deterioration; Development; Elastic Fiber; Elastin; Endopeptidases; Environmental Risk Factor; Enzymes; Evaluation; Extracellular Matrix; Family member; Fiber; Fibroblasts; Follow-Up Studies; Future; Gene Expression; Gene Mutation; Generations; Genes; Genetic; Genetic Determinism; Genetic Polymorphism; Glucocorticoid Receptor; Glucocorticoids; Goals; Haplotypes; Hereditary Disease; Human; In Vitro; Inflammation; Inflammatory; Inherited; Injury; Knockout Mice; Lead; Lung; Lung diseases; Lung volume reduction surgery; Measures; Methods; Minor; Monitor; Mus; Mutation; Outcome Measure; Patients; Peptide Hydrolases; Population; Predisposition; Principal Investigator; Process; Protease Inhibitor; Pulmonary Emphysema; Pulmonary function tests; Recruitment Activity; Regulation; Resources; Respiratory physiology; Risk; Risk Factors; Role; Sampling; Sampling Studies; Severities; Smoke; Smoking; Smoking History; Staging; Structure of parenchyma of lung; Supravalvular aortic stenosis; Syndrome; Testing; Thinking; Transgenic Mice; Transgenic Organisms; Variant; cigarette smoke-induced; cigarette smoking; cigarette smoking; disease-causing mutation; early onset; gene function; genetic manipulation; genetic variant; in vivo; lung development; lung imaging; mouse model; programs; proteinase In; repaired; research study; tissue processing

Sensitivity to cigarette smoke-induced COPD is highly variable. Many genetic and environmental factors that are thought to be responsible for this natural variation, however, remain unidentified. Our preliminary results suggest that the level of elastin in the lung is critical for normal lung development and for timely and efficient repair following injury. When elastin levels are below a critical threshold, repair is unproductive and the lungs are more prone to develop COPD. Moreover, we have found that patients with mutations in the elastin gene (ELN) develop severe, very early onset bronchiectasis, emphysema and end-stage lung disease. Rare variants of elastin could also predispose to enhanced lung damage by affecting the quality of the elastic fiber. In this case, minor alterations in elastin processing or assembly could support normal lung development and function but result in fibers that have increased susceptibility to degradation by proteases. The central hypothesis of this proposal is that the quality and quantity of pulmonary elastin is a critical factor in determining susceptibility to cigarette smoke-induced lung damage, leading to COPD. This hypothesis is supported by preliminary data indicating that both quantitative and qualitative deficiency in elastin can predispose to smoke-induced emphysema in both animal models and in inherited syndromes in humans caused by ELN mutations. The goal of this proposal is to uncover the mechanisms by which elastin defects result in COPD, and to assess mutations and variants in ELN as risk factors of COPD. To achieve these goals we propose the following specific aims: Aim 1. To test if human genetic diseases caused by mutations in ELN are associated with an increased risk of COPD. Aim 2. To test whether genetic variants present in the normal population (a) alter ELN function and (b) are associated with quantitative outcome measures in patients with severe emphysema. Aim 3: To test if lower than normal levels of lung elastin resulting from genetic or environmental factors lead to increased susceptibility to COPD. Aim 4. To test if qualitative alterations in pulmonary elastin arising from rare elastin variants contribute to COPD susceptibility.

对香烟烟雾诱导的COPD的敏感性是高度可变的。许多遗传和环境因素 然而，被认为是造成这种自然变异的原因仍然没有得到确认。我们的初步 结果表明，肺中弹性蛋白的水平对于肺的正常发育和及时 损伤后的有效修复。当弹性蛋白水平低于临界阈值时，修复是无效的， 肺部更容易发展为COPD。此外，我们还发现， 弹性蛋白基因（ELN）发展严重的，非常早发型支气管扩张，肺气肿和终末期肺 疾病罕见的弹性蛋白变体也可能通过影响肺组织的质量而使肺损伤加重。 弹性纤维。在这种情况下，弹性蛋白加工或组装的微小改变可以支持正常的肺 发育和功能，但导致纤维对蛋白酶降解的敏感性增加。 该建议的中心假设是，肺弹性蛋白的质量和数量是一个关键因素。 决定吸烟引起的肺损伤易感性的因素，导致COPD。这 初步数据支持了这一假设，表明在数量和质量上都存在缺陷， 在动物模型和遗传性综合征中，弹性蛋白都能使吸烟引起的肺气肿易感。 由ELN突变引起的人类疾病。这项提案的目标是揭示弹性蛋白 ELN的突变和变异导致COPD，并评估ELN的突变和变异作为COPD的危险因素。实现 这些目标，我们提出以下具体目标：目标1。为了测试人类遗传疾病是否由 ELN突变与COPD风险增加相关。目标二。为了测试基因变异是否 存在于正常人群中（a）改变ELN功能和（B）与定量结果相关 严重肺气肿患者的治疗措施。目的3：测试肺弹性蛋白是否低于正常水平 遗传或环境因素导致对COPD的易感性增加。目标4。以测试是否 由罕见弹性蛋白变异引起的肺弹性蛋白质的改变有助于COPD 易感性