We recently initiated experiments to test the hypothesis that familial aortic aneurysms are caused by mutations in the type III procollagen gene. We found that the first family we used to test the hypothesis proved positive. Therefore, we propose here to test the hypothesis further and develop simple DNA tests that can be used to identify members of families predisposed to develop aortic aneurysms so that the patient can be monitored by non-invasive procedures and preventative surgery can be carried out before the aneurysms rupture. Specifically, we propose to: (1) Collect fibroblasts from 50 to 100 patients with aortic aneurysms. (2) Determine whether or not the patients had mutations in the type Ill procollagen gene. (3) If mutations are found, prove that the mutations cause changes in the biological functions of type Ill procollagen. (4) Develop simple DNA tests based on polymerase chain reaction that can be used to identify family members predisposed to the development of the aortic aneurysms. (5) Develop procedures for more rapid detection of mutations in the type Ill procollagen gene. (6) In collaborative studies with other members of our Institute, prepare transgenic mice expressing mutated type Ill procollagen genes and determine whether the transgenic mice are useful models for defining molecular etiology of the aortic aneurysms and possible therapies for the disease. (7) If no mutation in type III procollagen gene is found in a given family with aortic aneurysms, we will move on to the next candidate gene, the second major structural component of aortic wall, elastin.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL045996-01A1
Application #
3365123
Study Section
Pathobiochemistry Study Section (PBC)
Project Start
1991-08-16
Project End
1995-07-31
Budget Start
1991-08-16
Budget End
1992-07-31
Support Year
1
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Thomas Jefferson University
Department
Type
Schools of Medicine
DUNS #
061197161
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Kuivaniemi, Helena; Ryer, Evan J; Elmore, James R et al. (2015) Understanding the pathogenesis of abdominal aortic aneurysms. Expert Rev Cardiovasc Ther 13:975-87
Sakalihasan, Natzi; Defraigne, Jean-Olivier; Kerstenne, Marie-Ange et al. (2014) Family members of patients with abdominal aortic aneurysms are at increased risk for aneurysms: analysis of 618 probands and their families from the Li├Ęge AAA Family Study. Ann Vasc Surg 28:787-97
Jones, Gregory T; Bown, Matthew J; Gretarsdottir, Solveig et al. (2013) A sequence variant associated with sortilin-1 (SORT1) on 1p13.3 is independently associated with abdominal aortic aneurysm. Hum Mol Genet 22:2941-7
Tromp, G; Kuivaniemi, H (2009) Developments in genomics to improve understanding, diagnosis and management of aneurysms and peripheral artery disease. Eur J Vasc Endovasc Surg 38:676-82
Elmore, James R; Obmann, Melissa A; Kuivaniemi, Helena et al. (2009) Identification of a genetic variant associated with abdominal aortic aneurysms on chromosome 3p12.3 by genome wide association. J Vasc Surg 49:1525-31
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Boddy, Amy M; Lenk, Guy M; Lillvis, John H et al. (2008) Basic research studies to understand aneurysm disease. Drug News Perspect 21:142-8
Valkkila, M; Melkoniemi, M; Kvist, L et al. (2001) Genomic organization of the human COL3A1 and COL5A2 genes: COL5A2 has evolved differently than the other minor fibrillar collagen genes. Matrix Biol 20:357-66
Wang, X; Tromp, G; Cole, C W et al. (1999) Analysis of coding sequences for tissue inhibitor of metalloproteinases 1 (TIMP1) and 2 (TIMP2) in patients with aneurysms. Matrix Biol 18:121-4
Kuivaniemi, H; Marshall, A; Ganguly, A et al. (1998) Fibulin-2 exhibits high degree of variability, but no structural changes concordant with abdominal aortic aneurysms. Eur J Hum Genet 6:642-6

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