The mechanical properties and gas exchange units of the lung are determined by the extracellular matrix (ECM) network laid down during development. The macromolecules most important for lung mechanics and structural integrity are collagen, elastin, and proteoglycans. The importance of elastin to lung development and homeostasis is evident from the consequences of elastin gene mutation. When elastin is not expressed because of loss of function mutations, the lung does not develop normally and the organism does not survive. With abnormal elastin or lower than normal elastin levels, lung function is compromised and susceptibility to diseases is enhanced. Elastin degradation is a key step in the pathogenesis of chronic obstructive pulmonary disease and elastin misassembly is associated with lung disease in several forms of cutis laxa. Exacerbating the disease process is the inability of lung cells to repair damaged elastic fibers, which leads to permanently compromised lung function and ongoing degenerative disease. Given the importance of elastin to lung development and homeostasis, it is surprising that our understanding of elastic fiber synthesis and repair remains incomplete. The work outlined in this project continues our studies of elastic fiber biology. New findings are presented that call into question existing paradigms about elastin assembly requirements and the involved players. To better understand how elastin assembly occurs during normal development and why elastin repair doesn't happen in disease, we propose to take a fresh look at elastic fiber organization based on new structural and genetic information that suggests a novel way of thinking about this complicated process. We will pursue the hypothesis that the initial stages of elastin assembly occur in a specialized intracellular compartment and that lipids contribute to elastic fiber formation both inside and outside the cell. We will also reevaluate several long-held ideas about the role of microfibrils in elastic fiber formation and growth.
Our specific aims are:
Aim #1 : Elucidate the temporal and spatial relationship of proteins involved in elastin synthesis and elastic fiber formation;
Aim #2 : Investigate a role for cellular lipids in elastin assembly;
Aim #3 : Characterize intracellular trafficking of elastic fiber proteins and determine how this defines elastic fiber assembly;
and Aim #4 : Understand how elastin gain-of-function mutations lead to human disease.
This project seeks to elucidate the molecular basis of elastic fiber assembly. These studies are important for understanding how mutations in elastic fiber genes lead to vascular and pulmonary disease.
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