METALLOTHIONEIN FUNCTION AND CARCINOGENESIS

这项研究的主要目标是利用遗传学方法， 确定：（a）金属硫蛋白（MT）是否在 哺乳动物发育和生理学，（B）MT的不同同种型是否 具有不同的功能;（c）MT是否可以在延缓 恶性转化 MT-I和MT-II基因在大多数人中表达。 器官，它们是由各种金属和激素诱导的，它们 可能也有类似的功能这些MT将受到以下因素的干扰： 胚胎干细胞中的同源重组，这些细胞将被 用于产生缺乏MT-I、MT-II或两种同种型的小鼠。 的影响 这些突变对正常发育和生理反应的影响， 考察小鼠过度表达MT-I或MT-III（正常情况下不常见的MT）， 仅在大脑中表达）是通过显微注射 这些基因的标记版本，两侧是假定的基因座控制， MT基因座的区域。这些转基因小鼠将用于确定 如果MT的过量或异位表达影响发育或生理。 然后将表达降低或升高水平的MT的小鼠与 两种不同的转基因小鼠品系， 肝细胞癌 如果MT在延缓肿瘤发生中起作用， 那么我们预测小鼠体内的肝肿瘤会发展得更慢， 表达过量MT的小鼠中， 山

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.