Molecular mechanisms of elastic fiber formation

弹性纤维为反复拉伸的组织提供弹性，如大动脉、肺、皮肤和弹性韧带。探索计划的长期目标是了解弹性纤维形成的基本机制，并利用这些信息来促进需要弹性的新材料的产生。该计划的总体目标是破译基本成分的性质以及它们彼此之间和与细胞之间的功能关系，并分析如何利用这些机制形成完全功能的弹性纤维。*未来五年将专注于两种辅助蛋白质在弹性纤维形成中的作用，即纤维蛋白-4和潜在转化生长因子结合蛋白-4。这两种蛋白质都被证明是形成弹性纤维的关键成分。然而，这些角色的结构和机制基础尚不清楚。我们已经证明，纤毛蛋白-4通过硫酸肝素与细胞发生强烈的相互作用。我们的目标是确定细胞受体和纤维蛋白-4与细胞相互作用的弹性形成功能。我们还确定了纤毛蛋白-4与LTBP-4强烈相互作用并触发构象变化。我们的目标是了解这些结构变化，确定相互作用部位，并破译LTBP-4/纤维蛋白-4复合体在弹性纤维形成中的功能。为了解决这些问题，我们将采用最先进的生化和细胞培养方法的结合，使用尖端的现代仪器，这为年轻科学家的培训提供了良好的基础。*我们预计在未来五年从这些新目标中获得的信息将一方面加强我们对弹性纤维形成的基本机制的理解。另一方面，需要更长期的成果，才能在获得先进的弹性生物和纳米材料方面产生新的可能性。

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.**