We characterized apolipoprotein B (apoB) expression during rat development, and reported the first in vivo correlation between apoB mRNA editing activity and the expression of an RNA editing protein (REPR). We demonstrated that the normal development of apoB mRNA editing requires thyroid hormone (T3), and that T3 modulates REPR mRNA levels. We cloned the tissue specific expression of a human homologue to rat REPR; this putative human form of REPR gene contains a zinc-finger domain with 100% homology to the transcription factor YY-1. Current laboratory studies include: (1) defining the regulatory elements of the rat and human REPR gene promoter; (2) examining the in vitro expression of REPR in liver, intestinal and HeLa cell lines; (3) developing transgenic and knockout REPR mice using a new methodology--RNA/DNA hybrids. With this procedure the RNA targets the hybrid to a specific region in the genome, the DNA portion is then able to undergo homologous recombination inserting the desired change within the genome. The method can now induce a single base change in cultured cells. In our clinical studies (1) we examined intestinal apoB mRNA editing in a cohort of 8 patients with premature coronary artery disease and 15 normal volunteers, and reported the first example of a defective mRNA intestinal editing associated with premature atherosclerosis; (2) we isolated mRNA from the adipose tissue of a child with lipoprotein lipase deficiency (LPL) and several normal patients,and collaborated in the quantitation of LPL transcription; we have observed that this case of LPL deficiency is secondary to a post-transcriptional defect in LPL expression; (3) we have initiated a collaboration with another section of LMTB in the characterization of IL-4 receptor expression in normal vs. activated macrophages (foam cells) in the atherosclerotic plaque; (4) a study has begun evaluating the effect of niacin, a lipid lowering drug, on the markedly atherogenic lipoprotein Lp(a) in patients with systemic lupus erythematosus(SLE); (5) 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.
