The Role of Elastin and Elastic Fiber-Related Proteins in Vascular Development, Function and Homeostasis

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The formation of a blood vessel wall is a complex, coordinated process. Large vessels must have the ability to stretch and recoil to accommodate the pulsation of the blood as it is ejected from the heart. The protein responsible for this feature is elastin. Elastin is secreted by the muscle cells in the wall and assembled into sheets or laminae that alternate with the cells to form multiple layers. Over the years, a large number of proteins have been found to contribute to the assembly of elastic laminae, however, the specific function of each of these proteins remains to be determined. One method to learn about the function of a protein is to make a mouse that is missing the protein of interest. By studying the ultrastructure of the tissues in such mice, called knockout mice, one can begin to delineate the role of the knocked out protein in tissue assembly and/or function. In the field of elastic fiber biology, a large number of knockout mice have already been made by various research groups. For the most part, a detailed analysis of the elastin-rich tissues in these mice, such as blood vessels, lungs and skin, has not been conducted and there is additional novel and important information to be obtained from their study. In our research program, we will study several different mouse models for fibrillin-1 and fibulin-4, two proteins that are critical for elastic laminae formation. We will also generate a new mouse model for elastin, which will provide us with the ability to learn what cells are important for blood vessel development and how the cells assemble the elastin into the elastic laminae. Elastin is a unique protein, in that, it is only made up to young adulthood, after which time, no new elastin is produced. The proper assembly of elastic laminae in blood vessels and elastic fibers in lungs and skin is therefore a critical process since the elastin we produce early in our lives must last a lifetime. Thus, it is our long-term goal to understand how elastic laminae and elastic fibers are assembled in tissues, and how these structures may be damaged in injury or disease.