Marfan syndrome (MFS) is a congenital disorder of the connective tissue that is caused by mutations in fibrillin-1, the major structural component of extracellular microfibrils. We have originally hypothesized and subsequently demonstrated that flbrillin-1 mutations impair the sequestration of latent TGFp complexes in the extracellular matrix with deleterious consequence to cell performance. This seminal discovery has led to the realization that TGFp blockade is a productive new strategy to mitigate systemic manifestations in mouse models of MFS and perhaps in human pafients. We now present data that implicate MAPKs and BMPs as addifional contributors to organ-specific abnormalifies in mouse models of MFS. These exciting new findings are consistent with the emerging role of microfibrils in the extracellular storage of several TGFp superfamily members. They are also in line with the notion that TGFp and BMPs can signal through MAPK-mediated pathways and that MAPKs can influence Smad activity in response to environmental stress and tissue injury. We therefore hypothesize that flbrillin-1 mutations trigger a series of matrix-dependent events that disrupt the physiological balance of TGFp and BMP signaling in individual tissues, and that improper stimulafion of p38 MAPK activity (through TGFp and/or stress-response signals) exacerbates this disease-causing process Accordingly, the main focus of the present project is to evaluate the potential role of p38 and BMPs in the pathogenesis of aortic aneurysm and skeletal deformities in mouse models of progressively severe MFS Specifically, we propose to:
Aim 1 : Interrogate the contribufion of p38 activity to aortic aneurysm in Fbn1 mutant mice that are also defective in non-canonical TGFp signaling or are systemically treated with inhibitors of p38 or Smad2/3 signaling.
Aim 2 : Evaluate the role of unbalanced TGFp and BMP signaling in bone overgrowth using mice in which Fbnl deficiency is paired with loss of TGFp or BMP type II receptors, or with over-expression of a BMP antagonist. The proposed studies will complement and be informed by parallel investigations on the contribution to aortic aneurysm of ERK1/2 signaling (Project 1), latent TGFp activators (Project 2) and a structurally abnormal extracellular matrix (Project 3). Additionally, the unique reagents and imaging services of Core B will provide critical support to the work. Collectively, our efforts will shed new light on the complexity of the physiological roles that fibrillin-rich microfibrils play in organ formafion and function, in addition to providing evidence-based opportunities for therapeutic intervention in MFS and related disorders of the connective tissue.

Public Health Relevance

While promiscuous TGFp activity is central to MFS pathogenesis, other signaling events parallel or downstream of it contribute to disease progression in different organ systems. The proposed studies will further advance knowledge of MFS pathogenesis by identifying new biological targets for therapy as well as diagnostic biomarkers of aortic aneurysm and skeletal deformities, which are 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 #
5P01AR049698-09
Application #
8379274
Study Section
Special Emphasis Panel (ZAR1-MLB-F)
Project Start
Project End
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
9
Fiscal Year
2012
Total Cost
$292,232
Indirect Cost
$39,112
Name
Icahn School of Medicine at Mount Sinai
Department
Type
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
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

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