PROVIDED.Marfan syndrome (MFS) is characterized by multiple disorders of connective tissue, includingaortic aneurysm, ectopia lentis, and sclerosis and kyphosis, caused by mutations in the fibrillin-1(Fbn-1) gene. Recent evidence indicates that the pathological sequellae are not caused only bychanges in the structural functions of Fbn-1 but also by alterations in the regulation of thebioavailability of signaling molecules, such as TGF-[3 and BMP. For example, thedevelopmental emphysema observed in mice with decreased Fbn-1 expression is related toheightened levels of active TGF-[51 in this tissue.This proposal contains two aims directed at validating the hypothesis that certain tissue changesin MFS result from altered interactions of TGF-I3 and BMPs.
In Aim 1, we will identify theactivator of latent TGF-I] in the lungs or aortas of mice with an Fbn-1 deficit. This will be doneusing either in vitro cell or tissue culture approaches and selective inhibitors of TGF-13generation or by a novel genetic screen we have developed for the identification of TGF-I]activators.
In Aim 2, we will characterize the role of Fbn-1 in modulating the activity of BMP-7.We will first develop a sensitive cell-based bioassay for BMP-7. We will next utilize this assayto determine whether and how BMP interaction with Fbn-1 affects latent BMP-7 activation,protects BMP-7 from inhibition, and focuses BMP-7 at sites of action. The results of theseexperiments will validate portions of the new mechanistic view of MFS and potentially identifytargets for therapies for MFS.
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