MOLECULAR REGULATION OF LIVER REGENERATION

部分肝切除术后肝脏再生的能力提供了 研究细胞增殖的体内调节的独特系统， 基因表达。 控制因素的详细性质， 监管这一现象现在才开始浮出水面，似乎 代表了细胞内事件的复杂级联。 不寻常的能力 肝脏的再生对于它从许多疾病中恢复至关重要。 疾病状态以及手术和化学损伤。 完全是 依赖于正常静止细胞重新进入活动状态 细胞分裂。 本提案的主要目的是， 信使RNA（mRNA）的稳定性在某些表达中的作用 再生大鼠肝脏中的细胞周期依赖性基因产物。 我们 假设是mRNA稳定性的调节主要是 负责这些转录本在肝脏中的表达 再生 本提案的具体目的是：（1）确认 某些原癌基因（c-fos，c-myc， c-jun、ras基因家族和p53）参与细胞增殖 结果是稳定性的变化，而不是转录水平的变化。 率;（2）分离和表征特定的胞质因子， 调节这些基因产物的稳定性;（3）建立一个基因表达系统， 体外肝细胞培养系统研究转录后水平 基因表达的调节。 我们的最终目标是制定一个 机制模型来解释mRNA稳定性的调节， 再生大鼠肝脏 为了实现这些目标， 细胞和分子生物学技术的应用。 初始 研究将确定对照组中原癌基因mRNA的半衰期， 和再生肝脏。 这些结果将与mRNA进行比较。 其他细胞周期依赖性基因产物的半衰期，包括鸟氨酸 脱羧酶和组蛋白H4，以及肝脏特异性转录物， 白蛋白和去唾液酸糖蛋白受体。 仔细观察， 考虑到β 1间隙连接蛋白和P450 IIE 1 mRNA的稳定性， 与上面提到的相反， 肝脏再生的初期阶段。 拟议的研究将提供 重要的洞察力，了解参与的机制， 调节肝脏中的正常细胞生长以及可能其他 组织中 更重要的是，研究结果应该揭示出 参与调节异常细胞增殖的机制。

The ability of the liver to regenerate after partial hepatectomy provides a unique system to study the in vivo regulation of cell proliferation and gene expression. The detailed nature of the controlling factors which regulate this phenomenon are only now beginning to surface and appear to represent a complex cascade of intracellular events. The unusual ability of the liver to regenerate is critical for its recovery from a number of disease states as well as surgical and chemical injury. It is solely dependent on the reentry of normally quiescent cells into an active state of cell division. The major objective of this proposal is to characterize the role of messenger RNA (mRNA) stability in the expression of certain cell-cycle dependent gene products in the regenerating rat liver. Our hypothesis is that the modulation of mRNA stability is predominately responsible for the expression of these transcripts during liver regeneration. The specific aims of this proposal are, (1) to confirm that the increased mRNA expression of certain protooncogenes (c-fos, c-myc, c-jun, the ras gene family and p53) involved in cellular proliferation results from changes in stability rather than changes in transcriptional rate; (2) to isolate and characterize specific cytosolic factors which regulate the stability of these gene products; and (3) to establish an in vitro hepatocyte culture system to study that aspect of posttranscriptional modulation of gene expression. Our ultimate goal is to formulate a mechanistic model to explain the regulation of mRNA stability in the regenerating rat liver. In order to accomplish these aims, it will be necessary to apply techniques in both cell and molecular biology. Initial studies will determine the half-life of the protooncogene mRNAs in control and regenerating liver. Those results will be compared to the mRNA half-life of other cell-cycle dependent gene products, including ornithine decarboxylase and histone H4, as well as the liver-specific transcripts for albumin and the asialoglycoprotein receptor. Careful attention will be paid to the stability of the beta1 gap junction protein and P450IIE1 mRNAs, which in contrast to those noted above, significantly decrease during the inial phases of liver regeneration. The proposed studies will provide important insight into understanding the mechanisms involved in the regulation of normal cell growth in the liver as well as perhaps other tissues. More importantly, the results should shed light on potential mechanisms involved in the regulation of abnormal cell proliferation.