METALLOTHIONEIN FUNCTION AND CARCINOGENESIS

这项研究的主要目标是使用遗传方法来 确定：(A)金属硫蛋白(MT)是否在 哺乳动物的发育和生理，(B)MT的不同亚型 有不同的功能和(C)MTS是否能起到延缓作用 恶变。MT-I和MT-II基因在大多数 器官，它们可以被各种金属和激素诱导，而且它们 可能有类似的、一般的功能。这些MT将受到以下因素的干扰 胚胎干细胞中的同源重组，这些细胞将 用于产生缺乏MT-I和/或MT-II亚型的小鼠。的影响 这些对正常发育和生理反应的突变将是 检查过了。小鼠过度表达MT-I或MT-III(通常是一种不寻常的MT 仅在大脑中表达)是由微量注射 这些基因的标记版本两侧都有假定的基因控制 来自MT轨迹的区域。这些转基因小鼠将被用于确定 MT的过度或异位表达是否会影响发育或生理。 表达MT水平降低或升高的小鼠随后将与 两个具有发育易感性的不同转基因系小鼠 肝细胞癌。如果MT起到了延缓肿瘤形成的作用， 然后我们预测小鼠的肝脏肿瘤将发展得更慢。 在表达水平降低的小鼠中更快地表达过量的MT Mt.Mt.

The major goals of this research are to use genetic approaches to determine: (a) whether metallothioneins (MT) are essential during mammalian development and physiology, (b) whether different isoforms of MT have distinct functions and (c) whether MTs can play a role in retarding malignant transformation. The MT-I and MT-II genes are expressed in most organs, they are inducible by a variety of metals and hormones, and they probably have a similar, general function. These MTs will be disrupted by homologous recombination in embryonic stem cells and those cells will be used to generate mice lacking MT-I, MT-II or both isoforms. The effect of these mutations on normal development and physiological responses will be examined. Mice over-expressing MT-I or MT-III (an unusual MT normally expressed only in the brain) have been generated by microinjection of marked versions of these genes flanked by presumptive locus control regions from the MT locus. These transgenic mice will be used to determine if excess or ectopic expression of MT affects development or physiology. Mice expressing reduced or elevated levels of MT will then be crossed with two different transgenic lines of mice with predispositions to develop hepatocellular carcinoma. If MT plays a role in retarding tumorigenesis, then we predict that hepatic tumors will develop more slowly in mice expressing excess MT and more rapidly in mice expressing reduced levels of MT.