DEVELOPMENTAL AND HORMONAL REGULATION OF APOLIPOPROTEIN B GENE EXPRESSION

我们研究了载脂蛋白B （apoB）在大鼠体内的表达

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 the T3 modulates REPR mRNA levels. We cloned and characterized 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 studies include: (1) defining the regulatory elements of the rat REPR gene promoter; (2) sequencing the entirety of the human REPR homologue; (3) examining the in vitro expression of REPR in liver , intestinal, and HeLa cell lines. In collaboration with the Molecular Disease Branch of NHLBI, we are developing transgenic and knockout REPR mouse models to examine the physiologic consequences of REPR over and under expression. 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 artherosclerosis; (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. Finally 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 artherosclerotic plaque.