Elastogenesis in vertebrates

弹性纤维为脊椎动物组织提供弹性，脊椎动物组织经历反复拉伸，例如大动脉、肺、弹性韧带和皮肤。长期探索计划的目标是了解弹性蛋白生成的基本机制。我们采用三管齐下的方法，包括体外生化分析，细胞方法和体内实验。该计划的长期目标是通过破译相关成分的特性，它们彼此之间和与细胞的功能关系，以及这些机制如何在生物体中用于形成专门用于各种弹性组织的全功能弹性纤维来了解弹性发生。未来五年将集中于细胞外纤维蛋白和纤维连接蛋白在弹性机制中的作用。纤蛋白-4和纤蛋白-5已被证明是弹性纤维形成的关键。然而，这一作用的结构和功能基础在很大程度上是未知的。我们的目标是映射与已知的结合配体的相互作用位点，并确定新的未知的相互作用配体，这可能是重要的弹性纤维的形成。我们进一步提出确定这些纤维蛋白的细胞受体。结合位点、相互作用配体和细胞受体对弹性纤维形成的功能贡献将在各种细胞培养方法中确定。我们在实验室中获得的新数据表明，细胞外纤连蛋白在调节纤维蛋白和弹性蛋白中起着关键作用。我们将使用一个新产生的条件性纤连蛋白基因敲除小鼠模型来研究纤连蛋白在弹性蛋白生成中的作用。预计从该项目中获得的信息不仅将增强我们对弹性纤维形成的基本理解，而且还将有助于在获得合成先进生物和纳米材料方面产生新的可能性。

Elastic fibers provide elasticity to vertebrate tissues that undergo repeated stretch, such as the large arteries, lung, elastic ligaments and skin. The long term Discovery program goal is to understand the fundamental mechanisms of elastogenesis. We use a three-pronged approach including in vitro biochemical analyses, cell approaches, and in vivo experiments. The long term objective of the program is to understand elastogenesis by deciphering the properties of associated components, their functional relationships with each other and with cells, and how these mechanisms are used in an organism to form fully functional elastic fibers specialized for various elastic tissues. The next five years will focus on the role of extracellular fibulins and fibronectin in elastogenic mechanisms. Fibulin-4 and -5 have been shown to be critical for elastic fiber formation. The structural and functional basis for this role, however, is largely unknown. We aim to map interaction sites with known binding ligands and to identify novel unknown interaction ligands, which may be important for elastic fiber formation. We further propose to identify cell receptors for these fibulins. Functional contributions of binding sites, interaction ligands and cell receptors for elastic fiber formation will be determined in various cell culture approaches. We obtained new data in the lab demonstrating that extracellular fibronectin plays a critical role in regulating fibulins and elastogenesis. We will use a newly generated conditional fibronectin knockout mouse model to study the role of fibronectin in elastogenesis. It is expected that the information gained from this project will not only enhance our basic understanding of elastic fiber formation, but will also help to generate new possibilities in obtaining synthetic advanced bio- and nano-materials.