Molecular mechanisms of elastic fiber formation

弹性纤维为经受反复拉伸的组织提供弹性，例如大动脉、肺、皮肤和弹性韧带。长期探索计划的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特性及其相互之间和与细胞的功能关系，并分析这些机制如何用于形成功能齐全的弹性纤维。 未来五年将重点关注两种辅助蛋白在弹性纤维形成中的作用，fibulin-4和潜在转化生长因子结合蛋白（LTBP）-4。这两种蛋白质已被证明是弹性纤维形成的关键组分。然而，这些作用的结构和机制基础是未知的。我们已经表明，fibulin-4通过硫酸乙酰肝素与细胞强烈相互作用。我们的目的是确定细胞受体和弹性功能的fibulin-4与细胞的相互作用。我们还确定了fibulin-4与LTBP-4强烈相互作用并引发构象变化。我们的目的是了解这些结构变化，确定相互作用的网站和破译的LTBP-4/fibulin-4复合物在弹性纤维形成的功能。为了解决这些问题，我们将采用最先进的生物化学和细胞培养方法的组合，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。 我们希望在未来五年内从这些新目标中获得的信息一方面将增强我们对弹性纤维形成基本机制的理解。另一方面，从长远来看，需要这些结果来产生获得先进弹性生物和纳米材料的新可能性。

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.