Molecular mechanisms of elastic fiber formation

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Elastic fibers provide elasticity to tissues that undergo repeated stretch, such as large arteries, lung, skin and elastic ligaments. The long term Discovery program goal is to understand the fundamental mechanisms of elastic fiber formation and use this information to advance the generation of new materials that require elasticity. The overarching objectives of the program is to decipher the properties of essential components and their functional relationships with each other and with cells, and to analyze how these mechanisms are used to form fully functional elastic fibers.***The next five years will focus on the role of two accessory proteins in elastic fiber formation, fibulin-4 and latent transforming growth factor binding protein (LTBP)-4. Both proteins have been shown to be critical components in elastic fiber formation. However, the structural and mechanistic basis for these roles is unknown. We have shown that fibulin-4 interacts strongly with cells via heparan sulfate. We aim to identify the cell receptor and the elastogenic function of the fibulin-4 interaction with cells. We have also determined that fibulin-4 interacts strongly with LTBP-4 and triggers conformational changes. We aim to understand these structural changes, identify the interaction sites and decipher the function of the LTBP-4/fibulin-4 complex in elastic fiber formation. To address these questions, we will employ a combination of state of the art biochemical and cell culture methods using cutting edge modern instruments, which provide an excellent basis for the training of young scientists.***We expect that the information gained from these new aims over the next five years will on one hand enhance our understanding of fundamental mechanisms in elastic fiber formation. On the other hand, the results are needed in longer term to generate new possibilities in obtaining advanced elastic bio- and nano-materials.**