(1) We are evaluating an alternative gene therapy method using a new methodology, RNA/DNA hybrids, targeting cultured cells as well as utilizing the hybrids to create animal models of disease. The RNA and DNA portions have different functions, RNA targets the hybrid to a specific region in the genome, the DNA portion is thought to then induce a repair process to modify a single targeted base, resulting in the desired change within the genome. The method has been used to induce targeted single base genomic changes in cultured cells for three targets apolipoprotein B, hemoglobin and alkaline phosphatase. (2)Elevated high density lipoproteins (HDL) are associated with a decreases of coronary artery disease and low levels are associated with an increased risk. We have identified two new HDL binding proteins which may have important physiologic roles. One is a 95kD protein that has high affinity for HDL, apoA-I and apoA-II with rapid on and off rates and a wide tissue distribution. A second has been determined to be heat shock protein 60 (hsp60), a mitochondrial matrix chaperone. Antibodies to this protein are known to be associated with the development of atherosclerosis and are found in multiple diseases such as diabetes and systemic lupus erythematosus.This finding therefore provides a potential link between autoimmunity, lipid metabolism and atherosclerosis. (3) We have been evaluating the effect of lovastatin, a lipid lowering drug, on the markedly atherogenic lipoprotein Lp(a) in patients with systemic lupus erythematosus (SLE); another study is evaluating thyroid hormone induced changes in Lp(a) in thyroid cancer patients. During treatment for thyroid cancer, thyroid hormone levels are iatrogenically varied, allowing the effect of high and low levels of thyroid hormone on Lp(a) to be determined. We have been evaluating the effect of niacin, another lipid lowering drug, on the markedly atherogenic lipoprotein Lp(a). Other collaborative studies involve determining the lipid effect of IL-6 and IL-10 in patients. Both interleukins significantly reduced cholesterol, triyglcerides and apolipoprotein B.