TRANSGENIC ANIMAL MODELS OF HUMAN INHERITED DISORDERS

在许多情况下，自然发生的人类疾病的动物模型，特别是那些影响神经系统的动物模型，还没有被描述。我们正在通过将DNA注射到受精卵中的原核显微注射和通过将转基因小鼠胚胎干细胞引入囊胚期小鼠胚胎的基因打靶来产生转基因小鼠。在发现基因缺陷的情况下，将突变引入小鼠生殖系提供了一个独特的机会，可以产生具有适当表型的小鼠，以便研究疾病的发病机制和治疗。除了“零等位基因”或“基因敲除”小鼠的产生外，我们正在使用其他策略，如LOX/Cre系统，将微妙的突变引入小鼠的种系。转基因小鼠的基因在细胞(包括神经胶质细胞和神经元)、组织特异性和/或可诱导/可抑制启动子的控制下也正在产生中。NIMH转基因和靶向小鼠资源是兽医研究分会和临床神经科学分会(IRP，NIMH)合作建立的。建立了小鼠模型，并在这些转基因小鼠中表征了基因的发育和组织特异性表达。我们在NIMH内部和其他研究所的研究人员共同努力，以产生人类疾病的转基因小鼠模型，这提供了宝贵的工具，扩大了我们对人类疾病的理解，并将有助于评估新的蛋白质/酶替代、细胞移植和基因转移疗法。

In many cases naturally occurring animal models of human disorders, especially those affecting the nervous system, have not been described. We are generating transgenic mice by pronuclear microinjection of DNA into fertilized eggs and by gene targeting from the introduction of genetically modified murine embryonic stem cells into blastocyst stage mouse embryos. In cases where the gene defect has been identified, the introduction of mutations into the germ line of mice provides a unique opportunity to generate mice having appropriate phenotypes where disease pathogenesis and treatment can be studied. In addition to the generation of "null allele" or "knockout" mice, we are using other strategies, such as the LOX/CRE system, for the introduction of subtle mutations into the germline of mice. Transgenic mice with genes under the control of cell (including glial and neuronal), tissue specific, and/or inducible/repressible promoters are also being produced. The NIMH Transgenic and Targeted Mouse Resource has been established as a cooperative effort between the Veterinary Medicine Research Branch and the Clinical Neuroscience Branch, IRP, NIMH. Murine models are produced and the developmental and tissue specific expression of genes is characterized in these transgenic mice. Our collaborative efforts, both within the NIMH and with investigators in other Institutes, to generate transgenic mouse models of human disorders are providing valuable tools that extend our understanding of human disorders and that will be useful for the evaluation of new protein/enzyme replacement, cellular transplantation, and gene transfer therapies.