GENE EXPRESSION IN AGING LIVER

该项目：老年患者和动物研究的临床数据显示， 随着年龄的增长肝功能会逐渐下降然而，在这方面， 功能改变的细胞和分子基础 在衰老肝脏中的位置仍然是个谜。 其中一个原因是 大多数研究的基因显示出一些但不是剧烈的变化， 衰老 另一个挑战是找到体内模型系统， 可以操纵基因表达的相关变化。 衰老过程似乎对至少 两个肝脏特异性基因：α 2u-球蛋白和衰老标志物 蛋白质-2。 α 2u-球蛋白基因只在青春期后表达 仅在青春期前和衰老大鼠的肝脏中，而在成年大鼠中不存在 雄性大鼠 这两个基因的表达都被控制在 转录水平。 这两个基因在哺乳动物中大量表达， 因此，大鼠肝脏是研究其机制的良好模型 衰老如何影响肝脏基因表达 在这个提议中，我们首先假设基因的改变 通过衰老表达，是一种可逆的现象，与 整个机体的老化而不是肝细胞本身。 我们将通过将老年大鼠的肝细胞移植到 幼兽的脾脏和肝脏。 基于此 假设我们预计这两个基因的表达将是 通过将它们放入年轻的宿主中并消除“老年宿主”来改变 环境”。 我们的第二个假设是α 2u- 球蛋白基因表达受存在的反式激活因子调节， 在衰老动物的肝细胞核中。 这些 因子与存在于5'端的顺式作用元件相互作用， α 2u-球蛋白的侧翼区和抑制剂抑制了α 2u-球蛋白的表达。 这个基因的表达。 因此，在第二部分中，我们建议 实验来识别和比较这些因子的结合状态 在α 2u-球蛋白基因的5 '侧翼区。

THE PROJECT: Clinical data from elderly patients and animals studies show that there is a gradual decline in liver function with aging. However, the cellular and molecular basis of functional alterations that take place in aging liver is still a mystery. Among the reasons for this is that most of the genes studied show some but not drastic alterations with aging. Another challenge is to find an in vivo model system where age related changes in gene expression can be manipulated. The aging process seems to have a dominant regulatory effect on at least two liver specific genes: alpha 2u-globulin, and senescence marker protein-2. The alpha 2u-globulin gene is expressed only after puberty only in the livers of prepubertal and senescent rats but not in adult male rats. The expression of both genes are shown to be controlled at the transcriptional level. These two genes are expressed abundantly in rat liver and therefore they are excellent models to study the mechanisms how of aging influences liver gene expression. In this proposal, we first hypothesize that alterations in gene expression by aging, is a reversible phenomenon and directly related to the aging of the whole organism rather than the hepatocytes themselves. We will test this by transplanting hepatocytes from the old rats into the spleens and the livers of the young animals. Based on this hypothesis we expect that the expression of these two genes will be altered by placing them into the young hosts and eliminating the "senile milieu". Our second hypothesis is that transcriptional decline in alpha 2u- globulin gene expression is regulated by trans-activating factors present in the nuclei of the hepatocytes from the senescent animals. These factor interact with cis acting elements that are present in the 5' flanking region of the a 2u-globulin and inactivate or repress the expression of this gene. Therefore in the second part, we propose experiments to identify and compare the binding sties of these factors in the 5'flanking region of the a 2u-globulin gene.