The tunica media of the aorta is comprised of alternating layers of smooth muscle cells and elastic fibers (elastic laminae). The molecules and precise mechanisms involved in the formation, organization and maintenance of these layers has yet to be defined. Recently, we have generated a null mutation in the mouse fibulin-5 gene and observed a striking phenotype of systemic elastinopathy due to a disorganization of elastic fibers. Fibulin-5 belongs to a family of similar extracellular matrix proteins and possesses 6 Ca2+ - binding EGF repeats and a single RGD motif. Fibulin-5 is significantly up-regulated in vascular injury suggesting a role in cardiovascular development and remodeling. Solid-phase binding and immunolocalization studies have indicated that fibulin-5 is a Ca2+ -dependent tropoelastin binding protein. We hypothesize that (i) fibulin-5 provides a scaffold that is essential for organizing elastic fibers by connecting elastin to cell surface integrins, (ii) fibulin-5 functions as a negative regulator of neointima formation via an RGD-dependent and/or independent mechanism. To test this hypothesis, we propose the following specific aims: (1) to characterize the vascular defects in the fibulin-5 null mice; (2) to define the molecular and genetic interaction of fibulin-5 and elastin; (3) to explore the role of fibulin-5 in cardiovascular remodeling using a model of vascular injury in fibulin-5 null mice. Results from these studies will not only provide fundamental information concerning the role of fibulin-5 in elastic fiber formation, but will ultimately establish an important basis for future studies on fibulin-5 in vascular diseases, such as supravalvular aortic stenosis, atherosclerosis and aortic aneurysms.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL071157-01A1
Application #
6686873
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Program Officer
Goldman, Stephen
Project Start
2003-07-01
Project End
2008-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
1
Fiscal Year
2003
Total Cost
$321,600
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Biochemistry
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
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Budatha, Madhusudhan; Roshanravan, Shayzreen; Zheng, Qian et al. (2011) Extracellular matrix proteases contribute to progression of pelvic organ prolapse in mice and humans. J Clin Invest 121:2048-59
Huang, Jianbin; Davis, Elaine C; Chapman, Shelby L et al. (2010) Fibulin-4 deficiency results in ascending aortic aneurysms: a potential link between abnormal smooth muscle cell phenotype and aneurysm progression. Circ Res 106:583-92
Chapman, Shelby L; Sicot, F-X; Davis, Elaine C et al. (2010) Fibulin-2 and fibulin-5 cooperatively function to form the internal elastic lamina and protect from vascular injury. Arterioscler Thromb Vasc Biol 30:68-74
Wan, William; Yanagisawa, Hiromi; Gleason Jr, Rudolph L (2010) Biomechanical and microstructural properties of common carotid arteries from fibulin-5 null mice. Ann Biomed Eng 38:3605-17
Schluterman, Marie K; Chapman, Shelby L; Korpanty, Grzegorz et al. (2010) Loss of fibulin-5 binding to beta1 integrins inhibits tumor growth by increasing the level of ROS. Dis Model Mech 3:333-42
Yanagisawa, Hiromi; Davis, Elaine C (2010) Unraveling the mechanism of elastic fiber assembly: The roles of short fibulins. Int J Biochem Cell Biol 42:1084-93
Choi, Jiwon; Bergdahl, Andreas; Zheng, Qian et al. (2009) Analysis of dermal elastic fibers in the absence of fibulin-5 reveals potential roles for fibulin-5 in elastic fiber assembly. Matrix Biol 28:211-20
Yanagisawa, Hiromi; Schluterman, Marie K; Brekken, Rolf A (2009) Fibulin-5, an integrin-binding matricellular protein: its function in development and disease. J Cell Commun Signal 3:337-47
Cirulis, Judith T; Bellingham, Catherine M; Davis, Elaine C et al. (2008) Fibrillins, fibulins, and matrix-associated glycoprotein modulate the kinetics and morphology of in vitro self-assembly of a recombinant elastin-like polypeptide. Biochemistry 47:12601-13

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