DEVELOPMENTAL AND HORMONAL REGULATION OF APOLIPOPROTEIN B GENE EXPRESSION

我们研究了大鼠载脂蛋白B(ApoB)的表达 并首次报道了apoB基因在体内的相关性。 编辑活性和RNA编辑蛋白(REPR)的表达。 我们证明了apoB mRNA编辑的正常发展需要 甲状腺激素(T3)，并且T3调节Repr的mRNA水平。我们 人组织特异性表达基因的克隆和鉴定 与大鼠REPR同源；这种假定的人类形式的REPR基因包含 与转录因子YY-1有100%同源性的锌指结构域。 目前的研究包括：(1)定义大鼠的调节元件 (2)人REPRR基因的全长序列测定 (3)检测REPR在肝脏中的体外表达， 肠道细胞系和HeLa细胞系。与分子研究中心合作 NHLBI疾病分部，我们正在开发转基因和基因敲除Repr 用小鼠模型检查Repr Over和Repr的生理后果 在表达式下。在我们的临床研究中(1)我们检查了肠道 8例冠脉早搏患者的载脂蛋白B基因编辑 动脉疾病和15名正常志愿者，并报告了第一例 与早产相关的肠道编辑缺陷的基因 (2)我们从一名儿童的脂肪组织中提取了信使核糖核酸。 患有脂蛋白脂肪酶缺乏症(LPL)和几名正常患者，以及 合作对LPL转录进行量化；我们观察到 这例LPL缺乏症继发于转录后 LPL表达缺陷。最后，我们发起了与 LMTB研究IL-4受体特性的另一部分 正常巨噬细胞与活化巨噬细胞(泡沫细胞)在 动脉粥样硬化斑块。

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.