Elastin is the extracellular matrix protein that imparts the property of elasticity to the lung and blood vessels.Its importance to both tissues is absolute. Without elastin the organism does not survive. With abnormalelastin, tissue development and function are compromised. The component of arteries and the lung inhigher vertebrates that accounts for their elastic properties is the elastic fiber network. Ultrastructuralanalysis of elastic fibers identified two components: the protein elastin and fibrillin-containing microfibrils.Understanding how elastic fibers are formed, however, has been difficult. During the past funding period weshowed that elastic fiber assembly is more complicated and the players more numerous than previouslythought. Thus, the overall objective of this renewal application is to better understand the assemblypathway and investigate the expanding list of molecules that participate in the process. The experimentalapproach will utilize in vitro assembly models supported by live cell imaging to identify the proteins involvedin elastin assembly. We will also utilize quick-freeze, deep-etch electron microscopy to characterize elasticfiber assembly at the tissue level. Finally, we will build upon results obtained during the previous fundingperiod to better understand the molecular organization of fibrillin-containing microfibrils.
Our specific aims are: 1) Identify the spatial and temporal appearance and functional interactions of keyassembly proteins during the early stages of elastic fiber formation. 2) Investigate the underlyingmechanisms of autosomal dominant cutis laxa (ADCL) and the possibility that elastin assembly occursthrough different mechanisms in different tissues. 3) Characterize elastic fiber assembly and matrixultrastructure in intact tissues using DEEM. 4) Elucidate the molecular structure of fibrillin-containingmicrofibrils.
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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