Marfan syndrome (MPS) is a common connective tissue disorder caused by mutations In flbrillln-1, the major Structural component of extracellular microfibrils. We originally speculated and have subsequently demonstrated that flbrlllln-1 mutations Impair the sequestration of latent TGFB complexes In the extracellular matrix (ECM) with deleterious consequences to cellular performance. This seminal discovery has led to the realization that TGFB blockade (specifically through losartan-mediated antagonism of angiotensin II receptor I activity) is a productive strategy to mitigate systemic manifestations in mouse models of MFS and human patients. Our work has also identified additional disease-causing processes that represent potential new targets for treatment of MFS and that are the focus of this renewal application. The disease-causing processes that will be investigated in the next funding cycle Include developmentally-lmposed changes of endothelial cell fate secondary to promiscuous TGFB signaling (Project 1), cellular and extracellular events leading to constitutive TGFB activation (Project 2), matrix-Induced perturbations of aorta homeostasis and repair (Project 3), and improper p38 MAPK activity and unbalanced TGFB and BMP signaling in the vascular and skeletal systems, respectively (Project 4). These different aspects of MFS pathogenesis will be interrogated in mouse models of the disease that are also deficient In relevant signaling molecules or that are treated with Inhibitors of specific effectors. Mouse-based analyses will be complemented and expanded by in vitro studies of mutant cells and tissues. As In the past, the highly Integrated effort of our research program is based on the unique but overlapping hypotheses of the four projects, whose ultimate amalgamation will delineate how initial ECM alterations are translated into aberrant cellular responses in MFS. Furthermore, the specialized services of the Administrative Core (Core A) and the Imaging and Antibodies Core (Core B) will continue to provide critical support to the research activities of our Consortium.

Public Health Relevance

MFS represents a unique example of a monogenic disorder that has informed our understanding of tissue degeneration and our ability to mitigate disease progression using a drug-based therapy. The proposed studies will further advance this knowledge by identifying new biological targets for therapy, as well as prognostic biomarkers of vascular and skeletal manifestations, which constitute the major mortality and morbidity factors in MFS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Program Projects (P01)
Project #
5P01AR049698-10
Application #
8527709
Study Section
Special Emphasis Panel (ZAR1-MLB-F (M2))
Program Officer
Tseng, Hung H
Project Start
2002-12-01
Project End
2015-08-31
Budget Start
2013-09-01
Budget End
2015-08-31
Support Year
10
Fiscal Year
2013
Total Cost
$1,475,237
Indirect Cost
$184,901
Name
Icahn School of Medicine at Mount Sinai
Department
Pharmacology
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
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
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 49:2383-9
Smaldone, Silvia; Ramirez, Francesco (2016) Fibrillin microfibrils in bone physiology. Matrix Biol 52-54:191-7
Horiguchi, Masahito; Todorovic, Vesna; Hadjiolova, Krassimira et al. (2015) Abrogation of both short and long forms of latent transforming growth factor-β binding protein-1 causes defective cardiovascular development and is perinatally lethal. Matrix Biol 43:61-70
Dabovic, Branka; Robertson, Ian B; Zilberberg, Lior et al. (2015) Function of latent TGFβ binding protein 4 and fibulin 5 in elastogenesis and lung development. J Cell Physiol 230:226-36
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
Cook, Jason R; Clayton, Nicholas P; Carta, Luca et al. (2015) Dimorphic effects of transforming growth factor-β signaling during aortic aneurysm progression in mice suggest a combinatorial therapy for Marfan syndrome. Arterioscler Thromb Vasc Biol 35:911-7
Sengle, Gerhard; Sakai, Lynn Y (2015) The fibrillin microfibril scaffold: A niche for growth factors and mechanosensation? Matrix Biol 47:3-12
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:
Robertson, Ian B; Horiguchi, Masahito; Zilberberg, Lior et al. (2015) Latent TGF-β-binding proteins. Matrix Biol 47:44-53

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