TRANSGENIC ANIMAL MODELS OF HUMAN INHERITED DISORDERS

在许多情况下，自然产生的动物模型 人类疾病，特别是那些影响神经系统的疾病， 还没有被描述。我们正在通过以下方式产生转基因小鼠 DNA原核显微注射受精卵和通过基因 从转基因小鼠的引入开始打靶 胚胎干细胞进入囊胚期小鼠胚胎。在案件中 在已确定基因缺陷的情况下，引入 小鼠生殖系的突变提供了一个独特的机会 为了产生具有适当表型的小鼠 发病机制和治疗方法可以研究。除 一代“零等位基因”或“基因敲除”小鼠，我们使用的是其他 战略，如LOX/CRE系统，以引入 小鼠生殖系的微妙突变。转基因小鼠 细胞(包括神经胶质细胞和神经元)、组织控制下的基因 特定的和/或可诱导/可抑制的启动子也正在 制作。NIMH转基因和靶向小鼠资源 已经被建立为兽医之间的合作努力 医学研究分会和临床神经科学分会 IRP，NIMH。小鼠模型正在生产中，而 基因的发育和组织特异性表达是 这些转基因小鼠的特征。我们的合作努力， NIMH内部和其他研究所的调查人员，以 产生人类疾病的转基因小鼠模型 提供有价值的工具，扩展我们对人类的理解 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。

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 being 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.