Muscling in on atherosclerosis

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A new collaboration between the Hoechst–ARIAD Genomics Center (Cambridge, MA, USA) and the Center for the Prevention of Cardiovascular Disease (CPCD, Harvard School for Public Health, Boston, MA, USA) will use functional genomics to find targets for the development of new therapies for cardiovascular disease.Dr Arthur Lee (Director, CPCD), and his colleagues have developed a model for atherosclerosis based on the murine cell line Monc-1, in which proliferating cells are induced to differentiate into smooth muscle cells. A number of genes are switched on during this process and researchers at the CPCD have found that genes in aortic smooth muscle cells behave in a similar way. Our idea is that atherosclerosis can occur when the normal cells have been de-differentiated so they begin to proliferate. We are trying to find the genes that cause this proliferation,' explains Dr Mark Zoller (Director, Hoechst–ARIAD Genomics Center).The research teams led by Dr Zoller and Dr Lee plan to identify the genes differentially expressed in the differentiated and undifferentiated cells by hybridizing the mRNA produced by the cells to DNA chips. `The genes on the chips represent every known gene to date, from full-length cDNA sequences, genomic sequences, expressed sequence tags or partial cDNA sequences. The goal is to have a chip with one fragment from each gene,' explains Zoller. At present, the chips contain approximately 30–40% of known human and mouse genes and, if necessary, they can be biased towards genes expressed in specific tissues.Once the differentially expressed genes have been identified, cell culture systems and animal models will be used to investigate the effects of stimulating or inhibiting the expression of these genes. It will then be up to the drug development teams at Hoechst Marion Roussel and ARIAD Pharmaceuticals to design therapies to target these genes or the proteins they encode, thereby preventing vascular smooth muscle cell (VSMC) proliferation and atherosclerosis.Researchers at Hoechst Marion Roussel in Frankfurt are also attempting to characterize the signals produced by vascular endothelial cells that trigger proliferation of smooth muscle cells. VSMC proliferation is also closely involved in tumor angiogenesis, so it is quite possible that a useful byproduct of this effort will be compounds that block tumor neovascularization.