The long-term objective is to develop a better understanding of the cellular proliferation that leads to the lesions associated with atherosclerosis. An understanding of the cellular events in atherogenesis will be an important factor in elucidating the biological mechanisms responsible for the disease process.
The specific aims are to test the following hypotheses in female baboons that are heterozygous for G6PD: 1) that monotypism will be more frequent in fatty streaks of baboons than in those of hybrid hares (an alternative model), 2) that hypertension, in addition to moderate hyperlipidemia, will enhance the development of arterial lesions, 3) that a higher proportion of lesions will be monotypic in hypertensive individuals, 4) that monotypism will occur with equal frequencies in the large muscular arteries and in the aorta, 5) that monotypism will occur more frequently in lesions composed predominantly of smooth muscle cells and few monocyte-macrophages, and 6) that monotypism among the smooth muscle cells, as identified by monoclonal antibodies specific for G6PD isozymes, is the primary underlying basis of monotypic lesions. Forty heterozygous baboons will be made moderately hyperlipidemic by an atherogenic diet, and 20 of these also will be made hypertensive by renal artery stenosis. After 2.5 years, the baboons will be necropsied, and arteries will undergo pathological analyses. G6PD electrophoresis will be conducted on small samples of lesions and normal arterial tissue to determine extent of monotypism. Monoclonal antibodies that react specifically with each G6PD isozyme will be produced and used in immunohistochemical analyses of monotypism among the different cell types within tissue sections. This approach will allow us to determine, with a much higher degree of resolution than currently possible, how monotypic foci of cells develop.
|VandeBerg, J L; Williams-Blangero, S (1996) Strategies for using nonhuman primates in genetic research on multifactorial diseases. Lab Anim Sci 46:146-51|
|VandeBerg, J L; Aivaliotis, M J; Samollow, P B (1992) X-linked glucose-6-phosphate dehydrogenase (G6PD) and autosomal 6-phosphogluconate dehydrogenase (6PGD) polymorphisms in baboons. Biochem Genet 30:567-79|