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 从基因产物替代到基因治疗， 转移产生了对动物模型的日益增长的需求， 研究发病机制和治疗方法。 大 人类遗传疾病的自然发生对应物的储存库 在动物中没有得到充分利用，主要是因为缺乏 提供所需的特殊研究，以确定 动物遗传疾病，并确定其与人类的同源性 遗传病 在以往的资助期内，我们已证明 这样的中心价值。 该项目的目标是继续 提供一个国家转诊中心， 表征和传播有用的新的人类动物模型 遗传病 本提案的重点将放在单基因人类 先天性代谢缺陷可能通过基因治疗得到纠正。 的 在各种物种中寻求动物模型，包括鼠，猫， 犬，将是这些人类疾病的真正同系物（涉及同源 基因位点，并具有与人类相当的疾病特征 疾病）。 该中心将提供咨询和实验室研究 有前途的新模式，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 活组织检查和死后标本。 家庭和育种研究将是 用于定义继承模式。 新车型将在 以细胞的形式提供给一般生物医学界 培养物、DNA、冷冻精液和繁殖群。 在选择的单基因 模型中未克隆基因的代谢紊乱 物种，我们将克隆正常和突变体的cDNA， 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.