Elastin is an important component of the extracellular matrix (ECM) in tissues such as lung, aorta, and elastic ligaments. Together with glycoprotein microfibrils, elastin forms extracellular fibers that provide the resiliency essential for normal tissue function. Although much is known about elastin's structure and function, relative little is understood about factors that regulate its synthesis during development or in tissue response to injury. Our research objectives are to determine how elastogenesis is initiated and regulated in connective tissue cells during development. Using the bovine ligamentum nuchae as a model to study elastin gene regulation, we have shown that the extracellular matrix secreted by the cell provides important """"""""feed-back"""""""" information to direct cellular differentiation and to stabilize the state of differentiation attained. We now wish to investigate in greater detail the role of environmental factors in elastin gene regulation. Our objective is to investigate the cellular regulation that occurs at each of the three transition events during development of elastic tissue: determination, differentiation, and maturation. The following questions define our specific aims: 1) When do cells become """"""""competent"""""""" to differentiate in response to inductive stimuli from ECM? 2) Does the inducing matrix play a molecularly instructive or simply permissive role in the cellular transition to elastin production? 3) Is DNA synthesis obligatory for differentiation? 4) Is expression of the elastin gene arrested in mature cells? 5) Can mature cells reinitiate high levels of elastin production to repair damaged tissue, and if so, what role does ECM play in cellular reactivation?

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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General Medicine A Subcommittee 2 (GMA)
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Washington University
Schools of Medicine
Saint Louis
United States
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