PROCESSING OF HUMAN APOLIPOPROTEIN-B MRNA

大多数脊椎动物的基因被分成多个外显子和内含子; 内含子很大，而外显子则很小。 平均尺寸 脊椎动物内部外显子的长度为137个核苷酸，很少超过300个核苷酸。 个核苷酸 偶尔，大外显子存在。 这项建议是 关注于研究剪接机制是否限制了外显子 大小;如果是这样，大外显子如何绕过正常的限制， 在剪接过程中的大小;以及大外显子是否有功能优势？ 一种天然存在的大外显子是鼠的外显子26， 人载脂蛋白B基因。 该外显子长度超过7kb。 人 肝脏，它被正确拼接以产生大的apo-bl00蛋白， 512 kd参与内源性脂质代谢。 人 在肠中，产生包括RNA编辑事件的mRNA。 编辑在外显子26内产生翻译终止密码子;翻译 产生252 kd的短apo-b48蛋白，参与 外源性脂质 编辑伴随着外显子内的多聚腺苷酸化 26. 该提案描述了旨在了解外显子 26在肝脏中被正确识别，或者在肝脏中被识别。 肠子 载脂蛋白-b的调节对正常人的 脂质代谢和人类心脏病。 了解机制 这两种形式的apo-b的产生应该会增加我们的 了解心脏病以及如何与之斗争。

Most vertebrate genes are split into multiple exons and introns; introns are large; exons, in contrast, are very small. The average size of a vertebrate internal exon is 137 nucleotides; very few exceed 300 nucleotides. Occasionally, large exons exist. This proposal is concerned with investigating if the splicing machinery restricts exon size; if it does, how do large exons by-pass the normal restrictions on size during splicing; and is there a functional advantage to large exons? One naturally occurring large exon is exon 26 of the murine and human apolipoprotein-b gene. This exon is over 7 kb in length. In human liver it is spliced correctly to produce the large apo-bl00 protein of 512 kd involved in the metabolism of endogenous lipids. In human intestine, a mRNA is produced that includes an RNA editing event. Editing produces a translational stop codon within exon 26; translation produces a short apo-b48 protein of 252 kd involved in the metabolism of exogenous lipids. Editing is accompanied by polyadenylation within exon 26. This proposal describes experiments designed to understand how exon 26 is correctly recognized in liver and alternatively recognized in intestine. The regulation of apolipoprotein-b is important to normal lipid metabolism and human heart disease. Understanding the mechanism whereby the two forms of apo-b are generated should increase our knowledge of heart disease and how to combat it.