My primary goal is to understand how tumor necrosis factor (TNF) receptors influence the development of atherosclerotic lesions. TNF is secreted from activated macrophages and results in a cascade of inflammatory and immune responses through binding to one or both of its receptors. We have mice deficient in the p55 receptor, deficient in the p75 receptor and deficient in both receptors. I will evaluate aortic lesion development in these mice to determine if this cytokine influences the development of atherosclerosis. Plasma lipids and glucose will be measured to determine if changes in circulating plasma components contribute to altered lesion development. TNF inhibits endothelial and smooth muscle cell replication. I will determine if there is altered cellular replication in the aortic wall of the receptor deficient mice. Additionally, there are numerous extracellular matrix proteins whose expression is influenced by TNF. The expression of these proteins in the receptor-deficient mice will be evaluated. These proteins are thought to play important roles in lesion development so if any differences are observed, a mechanism may be suggested for altered lesion formation. Results from these studies will increase our understanding as to how cellular alterations mediated by the TNF receptors can influence the development of heart disease. Furthermore, these experiments will evaluate how inflammatory responses and genetics contribute to the development of atherosclerosis.