Research Abstract:
A major goal of our research is to understand the complex process of extracellular matrix (ECM) secretion and assembly, with a particular focus on ECM proteins important to the cardiovascular system. We are interested in how ECM macromolecules assemble into complex polymers in the extracellular space, and how ECM influences the phenotype of cells, including the role of ECM in initiating differentiation and in maintaining appropriate gene expression in the differentiated phenotype. Our research involves identifying biologically active signals within ECM molecules that act directly on cell function. These studies include an interest in receptors for extracellular matrix.
The laboratory also has had a long-standing interest in vascular development and disease, particularly in understanding the development of the vessel wall and the recruitment and differentiation of smooth muscle cells. Gene array technology is used to identify genes differentially expressed in developing vessels and in response to hypertension. Using knockout and transgenic mice, we study how the overexpression or underexpression of key vascular proteins influences the development and function of the cardiovascular system. Gene arrays, in situ hybridization, and proteomic approaches are used to characterize vascular alteration associated with each animal phenotype, and physiological studies (vascular compliance, vascular reactivity, blood pressure, etc.) are used to document altered vascular function. We are also interested in human inherited diseases involving proteins of the elastic fiber, including supravalvar aortic stenosis (linked to mutations in the elastin gene), Marfan Syndrome (associated with mutations in fibrillin), and pulmonary and systemic hypertension.
Selected Publications:
Kozel BA, Rongish RJ, Czirok A, Zach J, Little CD, Davis EC, Knutsen RH, Wagenseil JE, Levy MA, Mecham RP. Elastic fiber formation: A dynamic view of extracellular matrix assembly using timer reporters. J Cellular Physiol 2006 207:87-96.
Broekelmann TJ, Kozel BA, Ishibashi H, Werneck CC, Keeley FW, Zhang L, and Mecham RP. Tropoelastin interacts with cell-surface glycosaminoglycans via its COOH-terminal domain. J Biol Chem 2005 280:42848-42855.
Kelleher CM, Silverman EK, et. al. A functional mutation in the terminal exon of elastin in severe, early onset chronic obstructive pulmonary disease. Am J Resp Cell Mol Biol 2005 33:355-362.
McLean SE, Mecham BH, Kelleher CM, Mariani TJ, and Mecham RP. Extracellular Matrix Gene Expression in the Developing Mouse Aorta. In: Advances in Developmental Biology and Biochemistry 2005 15:82-128.
Wagenseil J., Neurukar NL, Knutsen RH, Okamoto RJ, Li DY, and Mecham RP. Effects of elastin haploinsufficiency on the mechanical behavior of mouse arteries. Am J Physiol Heart Circ Physiol 2005 289:H1209-1217.
Last Updated: 08/17/2006 |