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疾病，尚未被描述。我们正在通过向受精卵中注入DNA的原核微注射和将转基因小鼠胚胎干细胞导入囊胚期小鼠胚胎的基因靶向来培育转基因小鼠。在已经确定基因缺陷的情况下，将突变引入小鼠的种系提供了一个独特的机会，可以产生具有适当表型的小鼠，从而可以研究疾病的发病机制和治疗。除了产生零等位基因或敲除小鼠外，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。基因受细胞（包括神经胶质和神经元）、组织特异性和/或诱导/抑制启动子控制的转基因小鼠也在生产中。NIMH转基因和靶向小鼠资源是由兽医学研究部门和临床神经科学部门，IRP， NIMH合作建立的。制备了小鼠模型，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内部以及与其他研究所的研究人员的合作努力，为产生人类疾病的转基因小鼠模型提供了有价值的工具，扩展了我们对人类疾病的理解，这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。-动物模型，原核显微注射，胚胎干细胞，囊胚，敲除小鼠，LOX/CRE系统，转基因，靶向小鼠，蛋白质/酶

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. - animal models, pronuclear microinjection, embryonic stem cells, blastocyst, knockout mice, LOX/CRE system, transgenic, targeted mouse, protein/enzyme