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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Program Projects (P01)
Project #
1P01AR049698-01A1
Application #
6808064
Study Section
Special Emphasis Panel (ZAR1-AAA-B (M2))
Program Officer
Tyree, Bernadette
Project Start
2004-07-01
Project End
2009-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
1
Fiscal Year
2004
Total Cost
$1,129,857
Indirect Cost
Name
Hospital for Special Surgery
Department
Type
DUNS #
622146454
City
New York
State
NY
Country
United States
Zip Code
10021
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