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.
| MacFarlane, Elena Gallo; Haupt, Julia; Dietz, Harry C et al. (2017) TGF-? Family Signaling in Connective Tissue and Skeletal Diseases. Cold Spring Harb Perspect Biol 9: |
| 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 |
| Sakai, Lynn Y; Keene, Douglas R; Renard, Marjolijn et al. (2016) FBN1: The disease-causing gene for Marfan syndrome and other genetic disorders. Gene 591:279-291 |
| 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: |
| Sengle, Gerhard; Sakai, Lynn Y (2015) The fibrillin microfibril scaffold: A niche for growth factors and mechanosensation? Matrix Biol 47:3-12 |
| Zilberberg, Lior; Phoon, Colin K L; Robertson, Ian et al. (2015) Genetic analysis of the contribution of LTBP-3 to thoracic aneurysm in Marfan syndrome. Proc Natl Acad Sci U S A 112:14012-7 |
| Robertson, Ian B; Horiguchi, Masahito; Zilberberg, Lior et al. (2015) Latent TGF-?-binding proteins. Matrix Biol 47:44-53 |
Showing the most recent 10 out of 78 publications
