ALPHA-FETOPROTEIN GENE REGULATION IN LIVER PATHOLOGY

损伤后，肝脏将进行受控的代偿性生长 使器官恢复到原来的质量 非常精确的机制 必须控制这一过程，感觉到生长的需要， 当它达到正确的大小。 然而，慢性再生或 用各种试剂的延长治疗将克服这种控制， 导致肿瘤发生。 肝再生伴随着 基因表达，包括甲胎蛋白（AFP）的表达 基因 AFP是一种所谓的胎儿抗原--在胎儿期表达， 出生后不表达，然后在肝再生过程中再次表达， 肿瘤发生 肝再生过程中AFP的表达水平 由遗传位点Rif控制，指定较低的AFP mRNA水平， C57 BL/6小鼠再生过程中。 这在生物学上的意义 观察结果是未知的，但它确实与I 对肿瘤发生的易感性。 长期目标是了解 受控再生生长期间基因调控与 不受控制的肿瘤生长。 AFP基因将被用作 在肝再生和肿瘤发生过程中表达的基因。 首先将确定在肝脏中AFP mRNA水平的增加是否与肝脏中AFP mRNA水平的增加有关。 再生是转录或转录后的结果 活动，通过直接测量所制作的记录本数量 随着时间 该基因座的哪些区域负责增加 肝再生过程中AFP的水平？携带转基因的小鼠 由驱动标记基因表达的AFP基因座区域组成 将在肝再生过程中检测其表达。 这一战略 将定位所需的区域，允许使用体外 鉴定和克隆基因相关因子的技术 表情 活性基因周围的染色质通常不同于 作为转录的结果，其核酸酶敏感性中的失活基因 因子结合 核酸酶超敏感位点将被定位和比较 在正常成人和胎儿肝脏中已经发现的。 是菌株 mRNA水平的依赖性差异是诱导机制的一部分， 或者它是独立的，反映了基因表达的其他差异。 这 将通过比较2种小鼠品系结果的实验来解决这个问题 C57 BL/6和C3 H/He。

After injury the liver will undergo controlled compensatory growth restoring the organ to its original mass. Remarkably precise mechanisms must control this process, sensing the requirement for growth and stopping it when the correct size is reached. However, chronic regeneration or prolonged treatment with a variety of agents will overcome this control, leading to tumorigenesis. Liver regeneration is accompanied by changes in gene expression, including the expression of the alpha-Fetoprotein (AFP) gene. AFP is a so called fetal antigen--expressed during fetal life, but not after birth, then expressed again during liver regeneration and tumorigenesis. The level of AFP expression in liver regeneration is controlled by the genetic locus, Rif, specifying lower AFP mRNA levels in C57BL/6 mice during regeneration. The biological significance of this observation is unknown, but it does correlate with differences in I susceptibility to tumorigenesis. The long term goal is to understand differences in gene regulation during controlled regenerative growth versus uncontrolled tumorigenic growth. The AFP gene will be used as a model for genes expressed during liver regeneration and tumorigenesis. It will first be determined if the increase in AFP mRNA levels during liver regeneration is the result of transcriptional or post-transcriptional activities, by direct measurement of the number of transcripts produced over time. Which regions of the locus are responsible for the increase levels of AFP during liver regeneration? Mice carrying transgenes consisting of regions of the AFP locus driving expression of a marker gene will be tested for expression during liver regeneration. This strategy will localize the region required, permitting the use of in vitro techniques to identify and clone the factor(s) responsible for gene expression. The chromatin surrounding active genes usually differs from inactive genes in its nuclease sensitivity, as a result of transcription factor binding. Nuclease hypersensitive sites will be mapped and compared to those already found in the normal adult and fetal liver. Are the strain dependent differences in mRNA levels a part of the mechanism of induction, or is it separate, reflecting other differences in gene expression. This will be addressed by experiments comparing results for 2 mouse strains C57BL/6 and C3H/He.