CONTROL OF ESTROGEN INDUCED PITUITARY HYPERPLASIA

RAT将被用作一个模型系统来解决一个基本问题 关于增长控制的。这里调查的特殊案件是控制 在雌激素存在的情况下脑垂体的生长，并与 雌激素在肿瘤形成和生殖生物学中的作用。慢性 雌激素治疗诱发大鼠垂体瘤的实验研究 Fischer 344，而其他菌株，如Holtzman或Brown挪威 抵抗这种诱导的。先前的遗传分析表明， 这种影响是由于两个或三个遗传位点的变异造成的。去调查 这种增长控制发生或未能发生的机制 负责的基因将被绘制、克隆和分析。费舍尔344和 一种抗癌品系，棕色挪威，将进行杂交，并将其后代 杂交产生一个F2群体。将对F2代动物进行测试 雌激素对垂体瘤的诱导作用及其数量性状 雌激素诱导的肿瘤块将使用简单序列重复进行定位 作为遗传标记和区间作图程序MapMaker QTL。这 还将使用数据来测量每个地图的影响程度 基因座与等位基因间的显性或加性关系 每一个轨迹。然后相关基因将被分离出来进行测序 通过位置克隆进行分析。基因组消减杂交 被称为遗传定向表征差异的技术 分析将被用来分离DNA序列的多态 定位基因座上的基因。这些多态将被用作分子 标签，以克隆与垂体瘤诱导有关的实际基因。

The rat will be used as a model system to address a fundamental question of growth control. The particular case investigated here is control of pituitary growth in the presence of estrogen and is relevant to estrogen's role in tumor formation and reproductive biology. Chronic treatment with estrogen induces pituitary tumors in the rat strain Fischer 344 while other strains, such as Holtzman or Brown Norway, are resistant to this induction. Previous genetic analysis suggested that the effect is due to variation at two or three genetic loci. To investigate the mechanism by which this growth control occurs, or fails to occur, the genes responsible will be mapped, cloned, and analyzed. Fischer 344 and a tumor resistant strain, Brown Norway, will be crossed and their progeny intercrossed to produce an F2 population. The F2 animals will be tested for estrogen induction of pituitary tumors and the quantitative trait of estrogen-induced tumor mass will be mapped using simple sequence repeats as genetic markers and the interval mapping program MAPMAKER QTL. This data will also be used to measure the magnitude of effect of each mapped locus and the dominance or additivity relationship between alleles at each locus. The relevant genes will then be isolated for sequence analysis by positional cloning. The genomic subtractive hybridization technique known as genetically directed representational difference analysis will be employed to isolate DNA sequence polymorphisms in the genes at the mapped loci. These polymorphisms will be used as molecular tags to clone the actual genes involved in induction of pituitary tumor.