This PPG has shown that certain clinical manifestafions of Marfan Syndrome (MFS), caused by mutations in fibrillin-1, are mediated by high levels of active TGF-B and that progression of selected phenotypes is blocked by the angiotensin type 1 (ATI) receptor antagonist losartan. Work from Project 2 (Rifkin) has shown that latent TGF-S is activated in cultures of MFS vascular smooth muscle cells (VSMCs), that the activator of latent TGF-B is an MMP, most likely MMP-9, and that TGF-B stimulates AT1 receptor expression. We propose a model in which defective matrix yields abnormal latent TGF-B sequestration followed by acfivafion, the active TGF-B sfimulates enhanced ATI receptor and MMP-9 expression, MMP-9 activates latent TGF-S, and ATI receptor signaling promotes confinued TGF-B expression. Thus, a cycle of activafion, enhanced expression, and activafion is established. However, the initiating event in this cycle is unknown, as are some ofthe interrelationships. This grant addresses three quesfions concerning TGF-B, ATI receptor, and MMPs in MFS.
In Aim 1, we will test whether perturbing the matrix results in the cycle of TGF-B formafion, ATI receptor expression up-regulation, and MMP-mediated latent TGF-B activation and if these changes are interrelated.
In Aim 2, we will use FACS to isolate and characterize cells of different lineages that contribute to aortic root VSMC populafions. Cells include cardiac nural crest, secondary heart field, mesoderm, and endothelium. Thus, we will determine whether or not abnormal cells in MFS arise from specific lineages, in which cells normally acfivate latent TGF-B, and have high levels of ATI receptor and MMPs. These results will be compared to those of Aim 1 in which cells generate these molecules because of failed matrix.
In Aim 3, we will generate MFS mice that are missing MMP-9 to establish if the in vitro activator MMP-9 is an in vivo acfivator. The completion of these aims will inform us as to the initiator of latent TGF-B activation, the cell that activates, and the nature ofthe in vivo activator.

Public Health Relevance

of this work is that an understanding the fundamental cause of celllular phenotypes in Marfan Syndrome will allow us to develop novel therapeutic approaches. We, the PPG, demonstrated this possiblity in the last grant cycle. In this new proposal, we will attempt to identify addifional targets, as it is probable that different people or different fissues with MFS will require addifional therapies.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAR1-MLB-F)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Icahn School of Medicine at Mount Sinai
New York
United States
Zip Code
Bellini, C; Korneva, A; Zilberberg, L et al. (2016) Differential ascending and descending aortic mechanics parallel aneurysmal propensity in a mouse model of Marfan syndrome. J Biomech 49:2383-2389
Smaldone, Silvia; Ramirez, Francesco (2016) Fibrillin microfibrils in bone physiology. Matrix Biol 52-54:191-197
Lee, Jia-Jye; Galatioto, Josephine; Rao, Satish et al. (2016) Losartan Attenuates Degradation of Aorta and Lung Tissue Micromechanics in a Mouse Model of Severe Marfan Syndrome. Ann Biomed Eng 44:2994-3006
Walji, Tezin A; Turecamo, Sarah E; DeMarsilis, Antea J et al. (2016) Characterization of metabolic health in mouse models of fibrillin-1 perturbation. Matrix Biol 55:63-76
Robertson, Ian B; Rifkin, Daniel B (2016) Regulation of the Bioavailability of TGF-? and TGF-?-Related Proteins. Cold Spring Harb Perspect Biol 8:
Doyle, Jefferson J; Doyle, Alexander J; Wilson, Nicole K et al. (2015) A deleterious gene-by-environment interaction imposed by calcium channel blockers in Marfan syndrome. Elife 4:
Cook, Jason R; Clayton, Nicholas P; Carta, Luca et al. (2015) Dimorphic effects of transforming growth factor-? signaling during aortic aneurysm progression in mice suggest a combinatorial therapy for Marfan syndrome. Arterioscler Thromb Vasc Biol 35:911-7
Cook, J R; Carta, L; Galatioto, J et al. (2015) Cardiovascular manifestations in Marfan syndrome and related diseases; multiple genes causing similar phenotypes. Clin Genet 87:11-20
Sengle, Gerhard; Carlberg, Valerie; Tufa, Sara F et al. (2015) Abnormal Activation of BMP Signaling Causes Myopathy in Fbn2 Null Mice. PLoS Genet 11:e1005340
Sengle, Gerhard; Sakai, Lynn Y (2015) The fibrillin microfibril scaffold: A niche for growth factors and mechanosensation? Matrix Biol 47:3-12

Showing the most recent 10 out of 76 publications