Attenuation of Estrogen-Induced Cell Proliferation

描述（由申请人提供）：本项目的长期目标是确定一种机制，通过这种机制，正常细胞在受到雌激素刺激时能够抑制生长。当大鼠长期接受雌激素治疗时，垂体细胞首先以细胞增殖增加作出反应，但几天后抑制增殖。虽然模型，如培养的细胞系和肿瘤丰富的类固醇刺激生长的研究，有一个系统，以研究随后的抑制生长的缺乏。将使用大鼠垂体的遗传学易处理模型系统研究这种生长控制现象。慢性雌激素暴露引起的大鼠垂体生长受一组称为数量性状基因座（QTL）的遗传因素控制，其中包括Edpm 3（大鼠3号染色体上的雌激素依赖性垂体质量QTL）。BN大鼠品系具有Edpm 3的生长抑制等位基因，并且即使连续暴露于雌激素10周也可以产生正常的生长控制反应。相反，F344大鼠品系具有Edpm 3的等位基因，其在类固醇依赖性垂体生长的控制中有缺陷。因此，雌激素治疗F344大鼠诱导不受控制的细胞增殖和泌乳素瘤。本项目的目的#1是开发原代细胞培养系统以研究Edpm 3的BN等位基因对雌激素诱导的细胞增殖的影响。(All迄今为止的工作都是在动物身上进行的）。目的#2是检验Edpm 3的BN等位基因减弱旁分泌生长控制的组分的假设。目的#3是鉴定其雌激素依赖性表达受Edpm3基因型影响的生长调节因子。

DESCRIPTION (provided by applicant): The long-term goal of this project is to identify a mechanism by which normal cells are able to restrain growth when stimulated by estrogen. When rats are chronically treated with estrogen, the cells of the pituitary first respond with increased cell proliferation, but then suppress proliferation after a few days. While models such as cultured cell lines and tumor abound for the study of stimulation of growth by steroids, there is a dearth of systems to investigate the subsequent suppression of growth. This growth control phenomenon will be investigated using the genetically tractable model system of the rat pituitary. Rat pituitary growth in response to chronic estrogen exposure is controlled by a group of genetic factors known as quantitative trait loci (QTL) which includes Edpm3 (estrogen-dependent pituitary mass QTL on rat Chromosome 3). The BN rat strain has growth suppressing alleles of Edpm3 and can mount the normal growth control response, even when continuously exposed to estrogen for 10 weeks. In contrast, The F344 rat strain has alleles of Edpm3 that are defective in control of steroid-dependent pituitary growth. Consequently, estrogen treatment of F344 rats induces uncontrolled cell proliferation and prolactinoma. Aim #1 of this project is to develop a primary cell culture system to investigate the effect of the BN allele of Edpm3 on estrogen-induced cell proliferation. (All work to date has been done in the animal.) Aim #2 is to test the hypothesis that the BN allele of Edpm3 attenuates a component of paracrine growth control. Aim #3 is to identify growth regulatory factors whose estrogen-dependent expression is affected by Edpm3 genotype.