Molecular Biology of Marfan Syndrome

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Marfan syndrome (MFS) is a common connective tissue disorder, caused by fibrillin-1 mutations, that is associated with severe skeletal, ocular, and cardiovascular complications including death due to ruptured aortic aneurysms. Our prior work has shown that many manifestations of MFS are caused byexcessive activation of and signaling by TGFbeta, a family of growth factors that regulate cell performance and survival. Loeys-Dietz syndrome (LDS) is a newly recognized and apparently common disorder caused by mutations in either of the two genes that encode the TGFbeta receptor (TBR). MFS and LDS are intimately related conditions, both in terms of clinical manifestations and pathogenetic mechanisms. We believe that the integrated study of both disorders will be particularly powerful. Our foundations derived from prior study of mouse models of MFS will provide a meaningful context within which to interpret newly created animal models of LDS. This will include a dedicated assessment of the lung, bone, skeletal muscle, aorta, and valve leaflets in TBR-deficient animals, both with and without treatment with TGFbeta neutralizing antibody. In contrast to MFS (where signaling defects are initiated by matrix perturbations), the cell-autonomous nature of the defect in LDS will allow rapid and definitive evaluation of other potentially relevant pathogenetic events (including altered angiotensin II (Angll), p38, ERK1/2 and JNK signaling) using cell culture systems and pathway-specific pharmacologic antagonists; positive results will allow for hypothesis-driven interrogation of tissues derived from Marfan mice and patients. We will evaluate for genetic interactions in TBR mutant animals that are also deficient for fibrillin-1 or that conditionally overexpress Smad7, a natural inhibitor of TGFbeta. These data will help to segregate features of MFS that manifest either structural or regulatory (TGFbeta-related) deficiencies of fibrillin-1. Mouse studies will compare the efficacy of treatment with a beta- adrenergic receptor blocker (that lowers hemodynamic stress) with that for losartan (that both lowers hemodynamic stress and antagonizes TGFbeta) in the treatment of LDS, a devastating disorder associated with vessel rupture and death in early childhood. Results will inform our linkage effort to identify genetic modifiers of the MFS using exceptional pedigrees that show discrete variation in disease manifestations. Taken together, these data will facilitate the development of novel and rational therapeutic strategies.