REFERRAL CENTER--ANIMAL MODELS OF HUMAN GENETIC DISEASE

治疗人类遗传性疾病的可能性越来越大 患者通过从基因产品替代到基因的各种方法 移植创造了对动物模型的日益增长的需求，在这种模型中 研究致病机制和治疗方法。大的 自然发生的人类遗传病的储存库 在动物身上没有得到充分的利用，主要是因为缺乏 无障碍中心提供所需的特殊研究以确定 动物的遗传性疾病及其与人类的同源性 遗传病。在之前的资助期中，我们已经展示了 这样一个中心的价值。该项目的目标是继续 提供一个全国性的身份鉴定转介中心， 有用的人类新动物模型的表征和传播 遗传病。这项提案的重点将是单基因人类 新陈代谢的先天缺陷，有可能通过基因治疗来纠正。这个 在各种物种中寻找动物模型，包括小鼠、猫和 狗，将是这些人类疾病的真正同源(涉及同源 并具有与人类相似的疾病特征 疾病)。该中心将提供咨询和实验室研究 有希望的新模式，包括检测和识别 异常代谢物、细胞遗传学和特殊病理学研究 活组织检查和尸检样本。家庭和养育方面的研究将 用于定义继承模式。将制造出已建立的新车型 以细胞的形式提供给一般生物医学社区 培养、DNA、冷冻精液和种畜。在选定的单基因中 该基因尚未在模型中克隆的代谢紊乱 物种，我们将克隆正常和突变的cdna，鉴定 突变，并使正常的cdna可用于基因转移研究。

The increasing possibilities for treating genetic disorders in human patients by approaches ranging from gene product replacement to gene transfer have created an increasing need for animal models in which to investigate pathogenetic mechanisms and approaches to therapy. The large reservoir of naturally-occurring counterparts of human genetic disease in animals has not been adequately utilized, largely because of the lack of accessible centers providing the special studies needed to identify genetic disorders in animals and establish their homology with human genetic diseases. In previous grant periods, we have demonstrated the value of such a center. The objective of this project is to continue to provide a national referral center for the identification, characterization, and dissemination of useful new animal models of human genetic disease. Emphasis in this proposal will be on monogenic human inborn errors of metabolism potentially correctable by gene therapy. The animal models sought among various species including murine, feline, and canine, will be true homologs of these human diseases (involve homologous gene loci and have disease characteristics comparable to the human disease). The center will provide consultation and laboratory studies of promising new models, including detection and identification of abnormal metabolites, cytogenetics, and special pathologic studies of biopsies and postmortem specimens. Family and breeding studies will be used to define modes of inheritance. Established new models will be made available to the general biomedical community in the form of cell cultures, DNA, frozen semen, and breeding stock. In selected monogenic metabolic disorders where the gene has not been cloned in the model species, we will clone the normal and mutant cDNA, characterize the mutation, and make the normal cDNA available for gene transfer studies.