GENE EXPRESSION IN AGING LIVER

项目：来自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， 功能改变的细胞和分子基础 在衰老的肝脏中所处的位置仍然是一个谜。其中一个原因是 大多数被研究的基因都显示出一些但不是剧烈的变化 衰老。另一个挑战是找到一种体内模型系统，其中年龄 基因表达的相关变化是可以操纵的。 衰老过程似乎对至少 两个肝脏特异基因：α2U球蛋白和衰老标记物 蛋白质2。α2U球蛋白基因只有在青春期后才会表达 仅在青春期前和衰老大鼠的肝脏中存在，而在成年大鼠中不存在 雄鼠。这两个基因的表达都被控制在 转录水平。这两个基因在人体内大量表达。 因此，它们是研究其机制的极佳模型。 衰老是如何影响肝脏基因表达的。 在这个提议中，我们首先假设基因的改变 衰老是一种可逆现象，与衰老有直接关系 整个生物体的衰老，而不是肝细胞本身的衰老。 我们将通过将老年大鼠的肝细胞移植到 幼年动物的脾和肝脏。在此基础上 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“衰老”来改变 环境“。 我们的第二个假设是阿尔法2U的转录下降- 球蛋白基因表达受存在的反式激活因子的调节 在衰老动物的肝细胞的细胞核中。这些 因子与5‘中存在的顺式作用元件相互作用 α2U-球蛋白侧翼区域并使其失活或抑制 这种基因的表达。因此，在第二部分，我们提出了 鉴定和比较这些因子的结合状态的实验 在α2U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.