ECTOPIC EXPRESSION OF THE PRION PROTEIN

该计划旨在为申请者的职业生涯做好准备。 作为神经退行性疾病领域的独立临床研究员 疾病。这项计划包括对 Pron病的细胞和分子生物学，Aspects课程工作 细胞生物学和生物化学专业，神经学临床经验 以神经退行性疾病为重点的疾病导致 运动障碍、住院医师和内科医生的教学 学生们。 该计划的核心是一个研究项目，旨在 探索与细胞类型相关的Pron病理生理学方面 产生普恩病毒，以及细胞类型之间相互作用的作用 参与了普恩病毒的繁殖。异位的转基因小鼠 Prion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/增强子区域与PrP相连 PrP的编码序列只在小鼠的颗粒细胞中表达 小脑、骨骼肌或胰岛的β细胞。 这些动物将被接种普恩病毒，并观察 自发性疾病的发展，以确定是否 体内需要多种细胞类型来繁殖普恩病毒，无论是 产生普鲁恩的细胞类型会影响应变特性 非神经细胞是否可以产生普恩病毒，如果可以，是否 它们对蛋白介导的病理变化很敏感。这些研究 可能会导致一种对普恩的快速生物检测。在这些动物身上的观察 也可能证明了Pron病的机制之间的相似性 和包涵体肌炎或Il型糖尿病。如果是这样，这些 动物可以作为这些条件的模型。申请人有 已开发出指导高水平PrP的转基因株系 胰腺骨骼肌和胰岛细胞的表达 小岛。 临床经验将包括在神经科诊所就诊。 教学经验将由指导和监督组成 神经科诊所的住院医生和医学生，演讲 在临床会议上，并指导医学生在 临床医学入门课程。

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.