The primary objective of this research program is to identify key events which occur early during the development of arteriosclerotic lesions and to elucidate the role environmental agents can play in modulating these events. The animal model we employ, the cockerel, is especially suited for these studies. It displays spontaneous, fibromuscular lesions (plaques) in the abdominal aorta which are very similar to coronary artery lesions in man. Among environmental agents, polycyclic aromatic hydrocarbons (PAH) have been particularly effective in our studies. To date, all PAH's with 4 or more rings that we have studied, including non-carcinogens, are very effective at accelerating plaque growth and development. This proposal represents an initial attempt to understand these effects at the molecular level. It also will permit the direct testing of the key implication of the Monoclonal Hypothesis, namely, that arteriosclerotic plaques behave similarly to benign smooth muscle cell lesions of the artery wall. We pose the following two questions: 1) Are there specific genes in plaque cells or in cells destined to become plaque cells whose activation and/or expression can be correlated directly with plaque development? 2) Do environmental agents which accelerate plaque development do so by activating dormant cellular genes and/or by enhancing their expression? We will use the techniques of molecular biology including transfection, restriction enzyme digestion, nick translation, Northern and Southern blotting, gene identification, and gene cloning. We will assess the degree of identity between a high molecular weight protein we have discovered in cockerel plaques and the high molecular weight platelet derived growth factor receptor; analyze the expression of that plaque protein at various stages of plaque development; measure differences in gene expression between plaques, normal arteries and other tissues of both cockerels and humans as well as between carcinogen-treated and untreated cells in culture; and determine whether plaque DNA shares characteristics with tumor DNA that it does not share with smooth muscle cell DNA. Positive results in these studies would indicate that there are similarities on the molecular level between events associated with the development of plaques and tumors and would thus provide direct support for the monoclonal hypothesis.
| Penn, A; Keller, K; Snyder, C et al. (1996) The tar fraction of cigarette smoke does not promote arteriosclerotic plaque development. Environ Health Perspect 104:1108-13 |
| Parkes, J L; Cardell, R R; Hubbard Jr, F C et al. (1991) Cultured human atherosclerotic plaque smooth muscle cells retain transforming potential and display enhanced expression of the myc protooncogene. Am J Pathol 138:765-75 |
| Parkes, J L; Hubbard Jr, F C; Penn, A (1990) Resistance of tumor-derived DNA to restriction enzyme digestion. Cancer Invest 8:169-72 |
| Penn, A (1990) Role of somatic mutation in atherosclerosis. Prog Clin Biol Res 340C:93-100 |
| Penn, A (1989) Molecular alterations critical to the development of arteriosclerotic plaques: a role for environmental agents. Environ Health Perspect 81:189-92 |
| Penn, A; Garte, S J; Warren, L et al. (1986) Transforming gene in human atherosclerotic plaque DNA. Proc Natl Acad Sci U S A 83:7951-5 |
