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Transgenic Mice for the Visualization of Dopamine Neurons in vivo

用于体内多巴胺神经元可视化的转基因小鼠

基本信息

批准号：
7684794
负责人：
WALTER C LOW
金额：
$ 7.55万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-15 至 2012-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7684794
关键词：
Affect Animal Model Animals Apoptotic Biological Assay Bradykinesia Brain Brain region Breeding Catecholamines Cell Count Cells Computer Simulation Cues Data Development Disease Dopamine Endotoxins Enzymes Evaluation Fireflies Future Grant Growth Factor Image Imagery Individual Inflammatory Life Lipopolysaccharides Luc Gene Luciferases Measurement Midbrain structure Modeling Monitor Mus Muscle Rigidity Nerve Degeneration Neurons Neurotoxins Oxidopamine Parkinson Disease Patients Photons Plasmids Play Process Regression Analysis Reporter Genes Research Role Screening procedure Staining method Stains Substantia nigra structure System Technology Testing Time Tissues Toxin Transgenes Transgenic Animals Transgenic Mice Transgenic Organisms Transplantation Tremor Tyrosine 3-Monooxygenase United States Validation base brain tissue charge coupled device camera dopaminergic neuron efficacy testing high throughput technology in vivo in vivo Model luciferin luminescence nervous system disorder neuron loss neurotoxic novel strategies offspring pars compacta promoter public health relevance small molecule tissue processing transmission process vector

项目摘要

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a neurological disorder caused by the progressive degeneration of dopamine neurons within the substantia nigra region of the brain. The causes of this degenerative process have yet to be clearly determined, however, many types of compounds such as growth factors, and anti-apoptotic agents have been proposed to protect against the loss of dopamine neurons. A major impediment to the assessment of these compounds is the lack of an in vivo model assay system for high through-put evaluation. Currently, the testing of these compounds requires that the brains of each animal be processed and analyzed over several weeks before the effects of these compounds can be determined by the quantification of dopamine neurons within the substantia nigra. We propose a new approach where the dopamine neurons within the substantia nigra can be visualized and quantified in individual animals be creating transgenic mice that express the firefly enzyme luciferase. The expression of this enzyme will be restricted to cells within the body that produce the enzyme tyrosine hydroxylase, the rate limiting enzyme in the synthesis of dopamine. This restricted distribution will be accomplished by using the tyrosine hydroxylase promoter to drive the expression of the luciferase gene. Cell specific expression of luciferase will enable us to visualize the quantify dopamine neurons in the substantia nigra of living mice, and provide a high through-put assay for screening compounds that affect dopaminergic neuron degeneration and survival. PUBLIC HEALTH RELEVANCE: Parkinson's disease (PD) is a neurological disorder characterized by tremor, rigidity, and bradykinesia. This is a progressively deteriorating condition that currently affects about 1.5 million people in the United States. At the present time, there is no cure for this disease. In our proposal, we intend to develop a line of transgenic mice that will enable us to visualize dopamine neurons in the living animal. Using this animal, we will be able to evaluate compounds that protect against dopamine neuron loss in a high throughput manner that will allow us to quickly screen many possible compounds. In addition, the development of this transgenic animal will allow us to study inductive cues that might be used to produce dopamine neurons that can be transplanted into patients with Parkinson's disease. As a consequence, this transgenic mouse could play an important role in developing new therapies for treating Parkinson's disease.

描述（由申请人提供）：帕金森病（PD）是一种神经系统疾病，由大脑黑质区域内多巴胺神经元的进行性变性引起。这种退化过程的原因尚未明确确定，然而，许多类型的化合物，如生长因子和抗凋亡剂已被提出来防止多巴胺神经元的损失。评估这些化合物的主要障碍是缺乏用于高通量评估的体内模型测定系统。目前，这些化合物的测试需要在几周内处理和分析每只动物的大脑，然后才能通过定量黑质内的多巴胺神经元来确定这些化合物的影响。我们提出了一种新的方法，其中黑质内的多巴胺神经元可以可视化和量化的个体动物创建转基因小鼠表达萤火虫酶荧光素酶。这种酶的表达将被限制在体内产生酪氨酸羟化酶的细胞中，酪氨酸羟化酶是多巴胺合成的限速酶。这种限制性分布将通过使用酪氨酸羟化酶启动子驱动荧光素酶基因的表达来实现。荧光素酶的细胞特异性表达将使我们能够可视化活体小鼠黑质中多巴胺神经元的定量，并为筛选影响多巴胺能神经元变性和存活的化合物提供高通量测定。公共卫生相关性：帕金森病（PD）是一种神经系统疾病，其特征为震颤、强直和运动迟缓。这是一种逐渐恶化的疾病，目前影响着美国约150万人。目前，这种疾病还没有治愈的方法。在我们的提议中，我们打算开发一系列转基因小鼠，使我们能够可视化活体动物中的多巴胺神经元。使用这种动物，我们将能够以高通量的方式评估保护多巴胺神经元损失的化合物，这将使我们能够快速筛选许多可能的化合物。此外，这种转基因动物的发展将使我们能够研究可能用于产生多巴胺神经元的诱导线索，这些神经元可以移植到帕金森病患者体内。因此，这种转基因小鼠可以在开发治疗帕金森病的新疗法方面发挥重要作用。