The Marfan syndrome (MFS) is a common, systemic disorder of connective tissue caused by mutations in fibrillin-1, the major constituent of extracellular microfibrils. In spite of advances leading to increased average life span for affected individuals, manifestations in multiple organ systems remain significant contributors to morbidity and mortality in the MFS. The long-term goal of this program is to translate basic research discoveries in matrix biology into productive therapeutic strategies for the management of individuals with MFS and related disorders of connective tissue. This meritorious goal will be pursued through the implementation of a comprehensive and multidisciplinary approach that integrates the scientific interest and experimental expertise of four leading laboratories in this and related research fields. The goal is solidly based on our previously established paradigm that fibrillin-1 deficiency results in dysregulation of TGFbeta super family signaling molecules. Our working model is that fibrillin-rich microfibrils regulate signaling events directly through specific molecular interactions, and indirectly through critical cell matrix interactions. This model will be investigated in genetically engineered mouse models of MFS using biochemical, cellular, ultrastructural, molecular, histological, physiological and phenotypic parameters. The main research themes of the Program include the study of (a) cellular events underlying aneurysm progression, (b) structural requirements for fibrillin-1 control of TGFbeta/BMP signaling, (c) mechanisms responsible for cytokine dysregulation in fibrillin-1 deficient matrices, and (d) involvement of other TGFbeta super family members in MFS pathogenesis and in vivo antagonism to explore potential therapeutic strategies. These themes will be pursued by four projects that are conceptually and experimentally integrated with and dependent upon one another. Overall progress of the research program relies on the specialized services of the Imaging and Antibodies Core and the administrative and clerical support of the Administrative Core.
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| 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 |
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