INTACT AND SCID MOUSE MODELS FOR GRAVES DISEASE

格雷夫斯病的完整和 SCID 小鼠模型

• 批准号: 2518319
• 负责人: TERRY Francis DAVIES
• 金额: $ 18.64万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-01-01 至 1999-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2518319
• 关键词: B lymphocyte; Graves disease; SCID mouse; T lymphocyte; antireceptor antibody; disease /disorder model; genetically modified animals; hormone receptor; human tissue; laboratory mouse; leukocyte activation /transformation; model design /development; recombinant proteins; thyrotropin; tissue mosaicism

DESCRIPTION (Adapted from Investigator's abstract): The investigator has previously focused on the development of new animal models of autoimmune thyroid disease to understand the immunopathology of thyroid antigen self-recognition. Using both intact and the severe combined immunodeficient (scid) mouse, the investigators have characterized the immune response to the receptor for thyroid stimulating hormone (TSHR), a major autoimmune target in the human thyroid gland. For example, patients with Graves' disease have TSHR autoantibodies which act as TSH agonists and induce thyroid hyperfunction. However, the investigators immunization of mice with recombinant human TSHR induced TSHR autoantibodies lacking in TSH agonist activity. They hypothesize that such an immune response was secondary to minor, but immunologically critical, differences in structure and folding of the human immunizing antigen compared to the mouse TSHR. In this competing renewal, they will develop two new animal models for Graves' disease and evaluate their B-cell and T-cell reactivities. The two specific aims are: 1) to prepare recombinant glycosylated mouse TSHR antigen in an insect cell system. Purified receptor will then be used to immunize intact mice, and they will evaluate their immunological and thyroid functional responses in this homologous system; 2) to develop transgenic mice expressing thyroidal human TSHR antigen and to carry out genetic crosses to produce hTSHR mice homozygous for the scid mutation. These scid-hTSHR mice will be injected with intrathyroidal lymphocytes and engrafted with thyroid tissue from patients with Graves' disease. Hence, the human TSHR-Abs will be able to interact with the transgenic human TSHR and induce thyroid overactivity. The construction of both an intact mouse model for Graves' disease as well as the reproduction of the human disease in scid mice will allow a series of intervention procedures to be pursued as potential therapeutic approaches to a common human disease.

描述（改编自研究者的摘要）：研究者已 此前专注于自身免疫新动物模型的开发 甲状腺疾病了解甲状腺抗原的免疫病理学 自我认知。 使用完整和严重联合免疫缺陷 (scid) 小鼠，研究人员已经表征了免疫反应 促甲状腺激素 (TSHR) 受体，一种主要的自身免疫性疾病 目标是人类甲状腺。 例如，格雷夫斯病患者 疾病具有 TSHR 自身抗体，可作为 TSH 激动剂并诱导 甲状腺功能亢进。 然而，研究人员对小鼠进行了免疫接种 重组人 TSHR 诱导缺乏 TSH 激动剂的 TSHR 自身抗体 活动。 他们假设这种免疫反应是继发于 结构和折叠方面存在微小但免疫学上至关重要的差异 人类免疫抗原与小鼠 TSHR 的比较。 在本次大赛中 更新，他们将开发两种新的格雷夫斯病动物模型和 评估他们的 B 细胞和 T 细胞反应性。 两个具体目标是： 1) 在昆虫细胞中制备重组糖基化小鼠TSHR抗原 系统。 然后纯化的受体将用于免疫完整的小鼠，并且 他们将评估他们的免疫和甲状腺功能反应 这个同源系统； 2）培育表达甲状腺的转基因小鼠 人类 TSHR 抗原并进行基因杂交以产生 hTSHR 小鼠 scid 突变纯合。 这些 scid-hTSHR 小鼠将被注射 与甲状腺内淋巴细胞并植入甲状腺组织 格雷夫斯病患者。 因此，人类 TSHR-Abs 将能够 与转基因人类 TSHR 相互作用并诱导甲状腺过度活跃。 格雷夫斯病完整小鼠模型的构建 因为人类疾病在 scid 小鼠中的繁殖将允许一系列 将采取干预程序作为潜在的治疗方法 一种人类常见疾病。