Animal models of dopamine-independent motor control

不依赖多巴胺的运动控制动物模型

• 批准号: 7884874
• 负责人: Xiaoxi Zhuang
• 金额: $ 18.96万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7884874
• 关键词: Adenylate Cyclase; Animal Model; Calcium; Calmodulin; Cells; Corpus striatum structure; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Development; Dopamine; Dopamine Antagonists; Dopamine D1 Receptor; Dopamine D2 Receptor; Dose; Dyskinetic syndrome; Feedback; G-Protein-Coupled Receptors; Glutamates; Goals; Lesion; Motor; Motor Activity; Motor output; Movement Disorders; Mus; Nerve Degeneration; Neurons; Parkinson Disease; Pathway interactions; Phenotype; Production; Property; Protein Isoforms; Receptor Cell; Replacement Therapy; Reserpine; Signal Transduction; Staging; Substantia nigra structure; Symptoms; Testing; Transgenic Mice; Transgenic Organisms; Work; adenylyl cyclase 1; adenylyl cyclase type V; base; dopaminergic neuron; effective therapy; gait examination; high risk; motor control; motor impairment; overexpression; promoter; public health relevance

DESCRIPTION (provided by applicant): In Parkinson's disease (PD), dopamine replacement therapies work well for the first a few years. However, in late stage PD, such therapies cause dyskinesia that is often more debilitating than PD itself. There is an urgent need to develop alternative approaches to treat motor impairment. We recently found that mice deficient for the striatum enriched adenylyl cyclase (AC) type V (AC5) display dopamine D2 receptor- independent motor control. However they are still dependent on dopamine D1 receptors. We hypothesize that over-expression of adenylyl cyclase type I (AC1) in striatal D1 receptor positive neurons will enable D1 receptor-independent motor control. We further hypothesize that double transgenic mice with both AC1 over-expression in D1 neurons and AC5 deficiency will display dopamine-independent motor control. We propose to generate these transgenic mice and test our hypotheses using dopamine antagonists, dopamine depletion and dopamine neuron lesions. We will examine motor functions using locomotor activity, akinesia test, gait analysis and rotarod. PUBLIC HEALTH RELEVANCE: We will generate transgenic mice with dopamine-independent motor control. Positive results will provide proof of principle and will guide the development of non- dopamine replacement based therapies for Parkinson's disease.

描述（由申请人提供）：对于帕金森病（PD），多巴胺替代疗法在最初几年效果良好。然而，在帕金森病晚期，此类疗法会导致运动障碍，这种运动障碍往往比帕金森病本身更令人衰弱。迫切需要开发治疗运动障碍的替代方法。我们最近发现纹状体富含腺苷酸环化酶 (AC) V 型 (AC5) 缺陷的小鼠表现出不依赖于多巴胺 D2 受体的运动控制。然而它们仍然依赖于多巴胺 D1 受体。我们假设纹状体 D1 受体阳性神经元中 I 型腺苷酸环化酶 (AC1) 的过度表达将实现不依赖于 D1 受体的运动控制。我们进一步假设，D1 神经元中 AC1 过度表达和 AC5 缺乏的双转基因小鼠将表现出不依赖多巴胺的运动控制。我们建议培育这些转基因小鼠，并使用多巴胺拮抗剂、多巴胺耗竭和多巴胺神经元损伤来测试我们的假设。我们将使用运动活动、运动不能测试、步态分析和旋转棒来检查运动功能。 公共健康相关性：我们将培育具有不依赖多巴胺的运动控制能力的转基因小鼠。积极的结果将提供原理证明，并将指导帕金森病的非多巴胺替代疗法的开发。