): The fibulins are an emerging family of extracellular matrix proteins characterized by the presence of tandem arrays of calcium-binding epidermal growth factor-like modules and a common C-terminal globular domain. Five members have been identified to date and they belong to two subgroups. The first two members, fibulin-1 and -2, are more related to each other by sequence identity and modular structure than to the three recently described members, fibulin-3, -4 and -5. All fibulins, except for fibulin-3, are highly abundant in the heart and blood vessel walls and thus may play essential roles in the cardiovascular system. Our laboratory first identified fibulin-2 and has subsequently studied fibulin-1 and -2 extensively. We and others have shown that fibulin- 1 and -2 are prominent components of heart septa and valves as well as aorta, pulmonary artery, and various large and small blood vessels. Fibulin-1 and -2 have also been shown to be present in the elastic fibers of the blood vessel walls where they colocalize with endostatin, the angiogenesis inhibitor. During embryonic development, fibulin-1 and -2 are highly specific markers for endocardial mesenchyme and smooth muscle cells of various types of blood vessels. The expression patterns of flbulin-1 and -2 overlap but there are distinct temporal and spatial differences. A critical role for fibulin-1 in blood vessel formation is demonstrated by our recent work showing that mice lacking fibulin- 1 are perinatally lethal as a result of massive bleeding. In this renewal application, we plan to continue studying the biological roles of fibulin-1 and fibulin-2 using biochemical approaches and transgenic mice generated by gene targeting, and to begin investigating the molecular mechanisms by which the cell-type specific expressions of fibulin genes are controlled. In addition, we propose to use flbulin-1 and -2 genes as markers to study in detail the development of heart septa and valves, great vessels and coronary blood vessels. The proposed studies will provide insights into the role of fibulins in human disease and the mechanism of cardiovascular development.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM055625-07
Application #
6607152
Study Section
Pathobiochemistry Study Section (PBC)
Program Officer
Flicker, Paula F
Project Start
1997-05-01
Project End
2005-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
7
Fiscal Year
2003
Total Cost
$298,528
Indirect Cost
Name
Thomas Jefferson University
Department
Dermatology
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Markova, Dessislava Z; Pan, Te-Cheng; Zhang, Rui-Zhu et al. (2016) Forelimb contractures and abnormal tendon collagen fibrillogenesis in fibulin-4 null mice. Cell Tissue Res 364:637-46
Tsuda, Takeshi; Wu, Jing; Gao, Erhe et al. (2012) Loss of fibulin-2 protects against progressive ventricular dysfunction after myocardial infarction. J Mol Cell Cardiol 52:273-82
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
Sicot, Francois-Xavier; Tsuda, Takeshi; Markova, Dessislava et al. (2008) Fibulin-2 is dispensable for mouse development and elastic fiber formation. Mol Cell Biol 28:1061-7
Dasouki, Majed; Markova, Dessislava; Garola, Robert et al. (2007) Compound heterozygous mutations in fibulin-4 causing neonatal lethal pulmonary artery occlusion, aortic aneurysm, arachnodactyly, and mild cutis laxa. Am J Med Genet A 143A:2635-41
Kobayashi, Naoyuki; Kostka, Gunter; Garbe, Jorg H O et al. (2007) A comparative analysis of the fibulin protein family. Biochemical characterization, binding interactions, and tissue localization. J Biol Chem 282:11805-16
Ji, Youngmi; Prasad, Nijaguna B; Novotny, Elizabeth A et al. (2007) Mouse embryo fibroblasts lacking the tumor suppressor menin show altered expression of extracellular matrix protein genes. Mol Cancer Res 5:1041-51
Bardin, A; Moll, F; Margueron, R et al. (2005) Transcriptional and posttranscriptional regulation of fibulin-1 by estrogens leads to differential induction of messenger ribonucleic acid variants in ovarian and breast cancer cells. Endocrinology 146:760-8
Chu, Mon-Li; Tsuda, Takeshi (2004) Fibulins in development and heritable disease. Birth Defects Res C Embryo Today 72:25-36
Tsuda, Takeshi; Markova, Dessislava; Wang, Hui et al. (2004) Zinc finger protein Zac1 is expressed in chondrogenic sites of the mouse. Dev Dyn 229:340-8

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