GENERATION OF ANIMAL MODELS OF HUMAN HEMOGLOBIN

人类血红蛋白动物模型的生成

• 批准号: 2332466
• 负责人: BAOLI YANG
• 金额: $ 3.53万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-07-19 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2332466
• 关键词: disease /disorder model; gene targeting; hemoglobin; hemoglobinopathy; hemoprotein structure; laboratory mouse; model design /development; sickle cell anemia; thalassemia

The research proposed is related to two of the most common inherited hemoglobinopathies in humans, beta thalassemia and sickle cell disease. Beta thalassemia is characterized by an absence or a reduction in the amount of the beta-globin chains, whereas in sickle cell anemia there is a single amino acid substitution in the beta-globin chain. These diseases cause considerable mortality and morbidity in humans. Naturally occurring mouse models of beta+ thalassemia have ben found by Skow et al. (1983) and an additional mouse model of beta+ thalassemia has been generated by gene targeting in this laboratory by Shehee et al. (1993). No models are available for beta+ thalassemia, a condition which resembles the most severe form of Cooley's anemia. Current genetic models for sickle cell disease are unsatisfactory because of the persistence of endogenous globin synthesis in the animals. I propose to use gene targeting to generate mice that are unable to synthesize any adult beta-globin, and which will therefore serve as models for Cooley's anemia. I also propose to replace both mouse adult alpha- and beta-globin genes with the corresponding human genes and thereby generate a mouse model in which mouse adult hemoglobins will be completely replaced by human sickle hemoglobin. These two models will not only enrich our knowledge about these two diseases, but should also be of great value in developing better treatment modalities for the two disease particularly those based on gene therapy.

提出的研究与两种最常见的遗传有关 人类血红蛋白病、β地中海贫血和镰状细胞病。 β地中海贫血的特点是缺乏或减少 β-珠蛋白链的数量，而在镰状细胞性贫血中， β-珠蛋白链中的单个氨基酸取代。 这些疾病 导致人类相当大的死亡率和发病率。 自然发生 Skow等人发现了β+地中海贫血小鼠模型。 （1983）和 基因产生了另一种β+地中海贫血小鼠模型 Shehee 等人在该实验室进行了靶向治疗。 （1993）。 没有型号 可用于β+地中海贫血，这种情况最类似于 严重的库利贫血。 目前镰状细胞的遗传模型 由于内源性珠蛋白的持续存在，疾病不令人满意 在动物体内合成。 我建议使用基因打靶来培育小鼠 无法合成任何成人β-珠蛋白，并且将 因此可以作为库利贫血的模型。 我也建议更换 小鼠成年 α 和 β 珠蛋白基因与相应的人类 基因，从而产生小鼠模型，其中小鼠成年血红蛋白 将被人类镰状血红蛋白完全取代。 这两个型号 不仅丰富了我们对这两种疾病的认识，而且应该 对于开发更好的治疗方式也具有重要价值 两种疾病，特别是那些基于基因治疗的疾病。