ECTOPIC EXPRESSION OF THE PRION PROTEIN

朊病毒蛋白的异位表达

• 批准号: 2460460
• 负责人: PATRICK J BOSQUE
• 金额: $ 8.64万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-09-30 至 2000-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2460460
• 关键词: bioassay; cell cell interaction; cell death; cell type; cellular pathology; cerebellum; gene expression; gene targeting; genetic enhancer element; genetic promoter element; genetic strain; genetically modified animals; granule cell; laboratory mouse; muscle cells; neurons; noninsulin dependent diabetes mellitus; pancreatic islets; prions; proteins

The program is designed to prepare the applicant for a productive career as an independent clinician researcher in the field of neurodegenerative disease. This program consists of supervised basic research into the cellular and molecular biology of prion disease, course work on aspects of cell biology and biochemistry, clinical experience in neurologic disorders with an emphasis on neurodegenerative conditions resulting in disorders of movement, and the teaching of residents and medical students. The core of the program consists of a research project designed to explore aspects of prion pathophysiology related to the cell types which generate prions, and the role of interactions between cell types involved in the propagation of prions. Transgenic mice in which ectopic expression of the prion protein (PrP) is directed to specific cell types are being developed. Animals carrying transgenes in which the promoter/enhancer region of a cell type specific gene is linked to a PrP coding sequence will express PrP only in granule cells of the cerebellum, skeletal muscle or beta-cells of the pancreatic islets. These animals will be inoculated with prions and observed for the development of spontaneous disease in order to determine whether multiple cell types are needed to propagate prions in vivo, whether the cell type in which prions are produced influences the strain properties of prions, whether non-neuronal cells can produce prions and, if so, if they are susceptible to prion mediated pathologic changes. These studies may lead to a rapid bio-assay for prions. Observations in these animals may also demonstrate similarities between the mechanism of prion disease and inclusion body myositis or type Il diabetes mellitus. If so, these animals may serve as models of these conditions. The applicant has already developed transgenic lines directing high levels of PrP expression to skeletal muscle and beta-islet cells of the pancreatic islets. Clinical experience will consist of attending in the neurology clinic. Teaching experience will consist of instruction and supervision of residents and medical students in the neurology clinic, presentations at clinical conferences, and preceptoring medical students in the Introductory to Clinical Medicine course.

该计划旨在为申请人的生产性职业做好准备 作为神经退行性疾病领域的独立临床研究者， 疾病该计划包括监督基础研究， 朊病毒病的细胞和分子生物学，课程内容 细胞生物学和生物化学，神经病学的临床经验 重点是神经退行性疾病， 运动障碍，以及居民和医疗教学 学生 该计划的核心包括一个研究项目，旨在 探索朊病毒病理生理学的各个方面， 产生朊病毒，以及细胞类型之间相互作用的作用 参与朊病毒的传播转基因小鼠中异位 朊病毒蛋白（PrP）的表达针对特定的细胞类型 正在开发中。 携带转基因的动物， 细胞类型特异性基因的启动子/增强子区与PrP连接 PrP编码序列仅在颗粒细胞中表达， 小脑、骨骼肌或胰岛的β细胞。 这些动物将接种朊病毒，并观察 自发性疾病的发展，以确定是否 需要多种类型的细胞来在体内繁殖朊病毒， 产生朊病毒的细胞类型影响菌株特性 朊病毒，非神经元细胞是否可以产生朊病毒，如果可以，如果 它们对朊病毒介导的病理变化敏感。这些研究 可能导致对朊病毒的快速生物测定。这些动物的观察结果 也可能证明朊病毒疾病机制之间的相似性 和包涵体肌炎或II型糖尿病。 如果是这样，这些 动物可以作为这些病症的模型。申请人已经 已经开发的指导高水平PrP的转基因品系 表达至骨骼肌和胰岛β细胞 小岛 临床经验将包括参加神经科诊所。 教学经验将包括指导和监督 住院医师和医学生在神经科诊所，介绍 在临床会议上，并指导医学生在 临床医学导论课程。