Genetic Determinants: Elastin Quality and Quantity

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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.