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IDENTIFYING AFR2--GENE REGULATOR IN LIVER PATHOLOGY

鉴定 AFR2——肝脏病理学中的基因调节因子

基本信息

批准号：
2856432
负责人：
MIRIAM H FEUERMAN
金额：
$ 19.11万
依托单位：
SUNY DOWNSTATE MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-01-01 至 2001-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2856432
关键词：
alpha fetoprotein artificial chromosomes carcinogenesis gene expression genetic polymorphism genetic strain laboratory mouse linkage mapping liver cells liver regeneration tissue /cell culture transcription factor transfection

项目摘要

DESCRIPTION: The alpha-fetoprotein (AFP) gene is an onco-fetal antigen, expressed in the developing fetus and under the pathological conditions of regeneration and tumorigenesis in the adult. The level of AFP gene expression during liver regeneration in mice is regulated by a genetically unlinked autosomal locus, Afr2. Inbred C57B1/6 mice express 8 to 10 fold less AFP during liver regeneration than wild type C3H/He mice. Lower AFP expression in regenerating liver may reflect other regulatory processes, as C57B1/6 mice are less susceptible to liver carcinogenesis than are C3H/He mice. From these and other genetic studies, it appears that the Afr2 gene is polymorphic. Since Afr2 regulates AFP expression, use of these different mouse strains provides a unique opportunity to identify a gene regulating AFP expression during liver regeneration. Using information from the Mouse Genome Project, in the first series of experiments, the Afr2 gene will be genetically mapped. Cloned DNA of this locus will be identified from a Yeast Artificial Chromosome library. Transcribed sequences will be isolated by exon-trapping and/or direction selection of cDNAs. Two criteria will be used to determine the likelihood that the transcribed sequences, as well as genes previously mapped to the locus, are Afr2: genetic linkage to the Afr2 gene and expression during liver regeneration. In the second series of experiments, a full length Afr2 cDNA clone will be prepared, transfected into a primary hepatocyte culture system, and tested for its ability to regulate AFP gene expression. Analysis of the activity of the two known Afr2 alleles will be compared. Identifying and isolating a clone of the Afr2 gene will provide a tool to study the relationships between developmental growth, controlled growth, and uncontrolled tumorigenic growth in the liver.

描述：甲胎蛋白(AFP)基因是一种肿瘤胎儿抗原，在发育中的胎儿中表达，在病理条件下成人的再生和肿瘤发生。甲胎蛋白基因水平小鼠肝再生过程中的表达受一种基因调控常染色体非连锁基因座，Afr2。近交系C57B1/6小鼠表达8至10倍肝再生过程中甲胎蛋白低于野生型C3H/He小鼠。较低的AFP 再生肝中的表达可能反映了其他调节过程，如 C57B1/6小鼠比C3H/He小鼠对肝癌的易感性较低老鼠。从这些和其他遗传学研究来看，Afr2基因似乎是多态的。由于Afr2调节AFP的表达，因此使用这些不同的小鼠品系为识别调控基因提供了独特的机会甲胎蛋白在肝再生过程中的表达。使用来自鼠标的信息基因组计划，在第一系列实验中，Afr2基因将被基因图谱。该基因座的克隆DNA将从一个酵母人工染色体文库。转录的序列将被分离出来通过外显子捕获和/或cDNA的方向选择。两个标准将是用来确定转录的序列以及先前定位到该基因座的基因是Afr2：与Afr2的遗传连锁肝再生过程中的基因和表达。在第二个系列中实验中，我们将制备全长的Afr2基因克隆，并将其导入进入原代肝细胞培养系统，并测试其能力调节甲胎蛋白基因表达。分析了两个已知的活动将比较Afr2等位基因。鉴定并分离出一个克隆的 Afr2基因将为研究二者之间的关系提供工具。发育性生长、受控生长和不受控制的致瘤生长在肝脏里。