An aneurysm is a dilatation of a blood vessel beyond twice its normal diameter. Despite surgical repair of more than 30,000 abdominal aortic aneurysms (AAA) each year (cost greater than 1 billion dollars), death from rupture and exsanguination of untreated AAA is among the 15 leading causes of death in the elderly. Moreover, the incidence of AAA appears to be increasing as does the proportion of women affected. The risk of rupture is virtually nil for small (less than 4 cm) AAA and increases exponentially for large (greater than 6 cm) aneurysms. Although small AAA are easily detectable by ultrasound, large scale screening programs are not considered cost-effective, in part, because there is currently no way to inhibit growth of small AAA. We have shown that aneurysm formation is not a simple process of attenuation. Rather, AAA is a complex remodeling process associated with increased expression of procollagen and a 2-5 fold increase in matrix protein content. The discontinuity of the medial elastin network in the earliest stages of AAA makes it clear that aneurysm growth ultimately dependents on the balance between synthesis and degradation of collagen. If the factors which regulate the balance between collagen synthesis and its degradation could be favorably affected, it may be possible to induce fibrosis and, thus, inhibit aneurysm growth. The focus of this proposal is the factors which regulate collagen synthesis and degradation in the aneurysmal aorta. The long term goal of this work is the pharmacological inhibition of aneurysm growth. The specific aims of this proposal are: 1) to determine tissue procollagen and interstitial collagenase mRNA levels in AAA, normal aorta, and aorta affected by atherosclerotic occlusive disease (AOD); 2) to localized procollagen and interstitial collagenase transcripts and candidate cytokines (TGF-beta 1 and IL-1 beta) known to modulate expression of these genes and determine their spatial relationship in aortic tissue sections; 3) to isolate the factors responsible for procollagen and interstitial collagenase expression in conditioned media and transfer their effect to target smooth muscle cells (SMC) in culture; 4) to attempt to block the effects of the conditioned media on the target SMC by specific blocking antibodies to candidate cytokines; 5) to correlate AAA growth rate with the relative expression of procollagen/interstitial collagenase. These specific aims will be accomplished using the following techniques: 1) Northern blot analysis of tissue RNA; 2) combined in situ hybridization and immunohistochemistry done on the same tissue section; 3) application of conditioned media from tissue minces to normal aortic SMC in culture followed by Northern blot analysis; 4) addition of monoclonal blocking antibodies to conditioned media followed by Northern analysis. Only after accurately characterizing collagen metabolism in human AAA, will it be possible to develop or select appropriate animal models. Ultimately, I believe this work will lead to the clinical testing of drugs that inhibit the progressive growth of small AAA.
|Effective start/end date||7/1/95 → 5/31/99|
- National Institutes of Health: $74,248.00
- National Institutes of Health: $113,272.00
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