Aneurysms rank 15th as a leading cause of death in the United States; and the incidence of AAA has increased seven-fold between 1951 and 1980. With the present trends toward aging of the population, it is obvious that aneurysms are a public health problem of substantial significance. Kern concepts of AAA pathogenesis have been proposed based on proteolytic destruction of aortic elastin by a metalloelastase. This group has been interested in familial clustering of AAA, and they have suggested X-linkage of a possible susceptibility factor. Considering that an ANTI-protease deficiency may be the underlying genetic susceptibility condition, it is interesting that the gene for tissue inhibitor of Metallo-Proteases (TIMP) has been assigned to the X-chromosome. The following program is proposed to explore the hypothesis that TIMP may play a role in AAA disease, in a sequence of steps to rule out abnormalities: 1) At the level of the gene; 2) In its transcription; and 3) In the translated gene product.
Sp Aim #1 : Study the variability of the known alleles of TIMP to rule out global abnormalities such as major deletions or insertions.
Sp Aim #2 : Determine the quantity and molecular weight of the TIMP transcript in mRNA purified from aneurysmal aortic tissue and cultured fibroblasts, and probe these tissues for the transcript by in-situ hybridization.
Sp Aim #3 : Characterize the gene product and its biological activity in a series of experiments based on the polyclonal antibody that they have developed in rabbit against recombinant TIMP. They will determine whether TIMP is detectable by radioimmunoassay and also by western blots in aneurysmal and control aortas, and also in fibroblasts cultured from AAA patients and controls. Immunohisto-chemical localization in these tissues will also be done to determine whether AAA modifies the level of TIMP expression and/or detection.
These aims are being implemented simultaneously and will influence each other. They support the long-term goals of developing methods for the early detection of susceptibility to aneurysm disease in man and modifying its natural history.
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