Elastogenesis in vertebrates

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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.