Marfan syndrome (MFS) is a heritable disorder of connective tissue with pleiotropic manifestations that include abnormalities in many organ systems, including the cardiovascular, skeletal, and ocular systems. When untreated, MFS often leads to premature death from cardiovascular complications, especially aortic dissection. Current treatment for MFS is limited and unfortunately, many patients with MFS still die of aortic dissection. Novel, more effective treatments are needed to reduce the morbidity and mortality associated with MFS. The design of new treatments necessitates that MFS be considered from a different perspective, especially its molecular pathogenesis. MFS is caused by heterozygous mutations in FBN1, the gene that encodes the matrix glycoprotein, fibrillin-1. Recent studies with mouse models of MFS indicate that enhancing fibrillin-1 production may be therapeutically beneficial, but no treatments exist to improve fibrillin-1 deposition in MFS patients. Given its considerable size (350 kD), large number of domains (59), and vast number of disulfide bonds (169), fibrillin- 1 is probably extremely difficult to fold. Many of the mutations that cause MFS affect cysteines and likely disrupt disulfide bonding and result in improper folding. We propose that most cases of MFS be viewed as a disease of protein folding and that therapies designed to increase the folding capacity of the endoplasmic reticulum (ER) will enhance fibrillin-1 deposition, reduce endoplasmic reticulum (ER) stress, and will prove beneficial in preventing or postponing aortic aneurysms. Our preliminary, in vitro results demonstrate that chaperone-based treatments improve fibrillin-1 deposition by MFS cells. The focus of this proposal is to investigate the specific mechanisms whereby chaperone treatments improve the extracellular matrix. We will also examine the extracellular matrix at the ultrastructural level and will assess the role of ER stress in MFS. ? ?
