TRANSGENIC ANIMAL MODELS OF HUMAN INHERITED DISORDERS

在许多情况下，人类疾病，特别是影响神经系统的疾病的自然发生的动物模型尚未被描述。我们正在通过将DNA原核显微注射到受精卵中以及通过将遗传修饰的小鼠胚胎干细胞引入囊胚期小鼠胚胎中进行基因靶向来产生转基因小鼠。 在已经鉴定出基因缺陷的情况下，将突变引入小鼠的生殖系提供了产生具有适当表型的小鼠的独特机会，其中可以研究疾病发病机制和治疗。 除了产生“无效等位基因”或“敲除”小鼠之外，我们还使用其他策略，例如LOX/CRE系统，用于将细微突变引入小鼠的种系中。也正在产生具有在细胞（包括神经胶质和神经元）、组织特异性和/或诱导型/阻遏型启动子控制下的基因的转基因小鼠。NIMH转基因和靶向小鼠资源已建立为兽医研究分支和临床神经科学分支，IRP，NIMH之间的合作努力。 产生小鼠模型，并在这些转基因小鼠中表征基因的发育和组织特异性表达。 我们的合作努力，无论是在NIMH和其他研究所的研究人员，产生人类疾病的转基因小鼠模型提供了有价值的工具，扩展我们对人类疾病的理解，这将是有用的新的蛋白质/酶替代，细胞移植和基因转移疗法的评估。

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.