Elastin is the major extracellular matrix component of large blood vessels. It is the protein responsible for the elastic recoil properties of these tissues and plays an important role in defining vascular will compartments. Several human diseases have recently been linked to mutations in elastin. The objective of this proposal is to better understand how these mutations alter the functional properties of the elastic fiber leading, ultimately, to vascular pathology. Our focus will be supravalcular aortic stenosis, an inherited obstructive vascular disease that causes significant narrowing of large systemic and pulmonary arteries. Recently, autosomal dominant SVAS has been linked to the elastin (ELN) locus on chromosome 7. There are two possible explanations for how mutations in elastin cause SVAS: 1) haploinsufficiency, where a half dose of normal elastin is being produced, or 2) abnormal elastic fibers arising from dominant negative elastin mutations. To test these possibilities, we propose to combine in vitro assays for elastin assembly with expression of mutant proteins in transgenic mice to identify the mechanism whereby mutant proteins alter elastic fiber structure and, ultimately, vascular function.
Our specific aims are; 1) To characterize ELN mutations in patients with sporadic and autosomal dominant SVS. 2) Determine if the mutant elastin allele is expressed in cells from patients with SVAS. 3) Ascertain whether mutant tropoelastin is capable of incorporating into, or disrupting normal elastic fibers. 4) Develop mouse models that express common ELN mutations found in SVAS and determine how these mutations alter vascular development and function. In addition to providing answers to the pathogenesis of SVAS, these studies will undoubtedly be instructive in identify domains of elastin that play a critical role in the normal function of this important protein.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
5P50HL061006-03
Application #
6444645
Study Section
Project Start
2001-04-10
Project End
2001-12-31
Budget Start
Budget End
Support Year
3
Fiscal Year
2001
Total Cost
Indirect Cost
Name
Washington University
Department
Type
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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