RECEPTOR MECHANISMS IN MOVEMENT DISORDER PATHOPHYSIOLOGY

基底神经节在正常运动的控制中起主要作用， 协同 基底神经节的病变导致运动障碍 从严重的运动不能、僵硬和震颤到肌张力障碍、舞蹈病和 弹道学 任何特定个体或疾病的病理学 这一过程取决于受影响的神经元的不同亚群。 抑制性氨基酸GABA是一种神经递质， 大多数纹状体，苍白球和黑质神经元，兴奋性 氨基酸（EAA），如谷氨酸作为神经递质， 皮质和丘脑向纹状体、丘脑底核和 多巴胺是黑质神经元的神经递质， 黑质纹状体通路，许多纹状体神经元携带腺苷A2 受体。 近年来，分子生物学的发展 使得许多受体亚型的基因得以克隆。 这使得 有可能确定这些新的分布和调节 在特定基底神经节神经元类型中克隆受体亚型， 它们在运动障碍的病理生理学中的作用。 该计划项目的建议书是一个合作的，多中心的 研究新克隆的受体亚型在动物中的作用的努力 运动障碍模型。 项目1将确定兴奋性氨基酸受体是否 在亨廷顿氏舞蹈症中， 疾病以及氨基酸受体基因的表达如何在 运动障碍的动物模型。项目2将研究地点 多巴胺受体亚型在纹状体、皮质和苍白球的分布。 项目3将研究腺苷A2受体的调节， 分子水平的研究进展，以及受体在动物体内的作用 运动障碍模型。 项目4将研究 氨基酸和多巴胺受体影响即刻早期基因表达 在运动障碍的动物模型中。 项目5将研究 氧化磷酸化缺陷可能在细胞凋亡中起作用。 亨廷顿病和帕金森病的发病机制 导致缓慢的兴奋毒性神经元变性。 这些项目将 得到行政、抗体生产和动物外科的支持 丹 阐明动物中受体调节的细节 人类疾病的模型将提供一个更完整的理解， 基底神经节电路在健康和疾病，并允许合理的 开发药物治疗这些疾病 对各种受体亚型具有选择性。

The basal ganglia play a major role in the control of normal movement and coordination. Lesions of the basal ganglia result in movement disorders ranging from severe akinesia, rigidity and tremor to dystonia, chorea and ballismus. The symptomatology in any particular individual or disease process depends on the distinct subgroups of neurons affected. The inhibitory amino acid GABA, is the neurotransmitter for the vast majority of striatal, pallidal and substantia nigra neurons, excitatory amino acids (EAA) such as glutamate serve as the neurotransmitters for cortical and thalamic efferents to striatum, subthalamic nucleus and substantia nigra neurons, dopamine is the neurotransmitter of the nigrostriatal pathway, and many striatal neurons bear adenosine A2 receptors. In the last several years molecular biologic advances have allowed the genes for many receptor subtypes to be cloned. This makes it possible to determine the distribution and regulation of these newly cloned receptor subtypes in specific basal ganglia neuronal types and their role in the pathophysiology of the movement disorders. This proposal for a program project is a collaborative, multicenter effort to study the role of the newly cloned receptor subtypes in animal models of movement disorders. Project 1 will determine if the excitatory amino acid receptors are preferentially localized on the neurons which degenerate in Huntington's disease and how the expression of amino acid receptor genes change in animal models of movement disorders. Project 2 will study the location of dopamine receptor subtypes in striatum, cortex and globus pallidus. Project 3 will study the regulation of adenosine A2 receptors at the molecular level in animal and human, and the receptor's role in animal models of movement disorders. Project 4 will study the factors by which amino acid and dopamine receptors affect immediate early gene expression in animal models of movement disorders. Project 5 will study the possibility that oxidative phosphorylation defects may play a role in the pathogenesis of Huntingtons's and Parkinson's diseases by processes leading to slow excitotoxic neuronal degeneration. These projects will be supported by administrative, antibody production and animal surgery cores. Elucidation of the details of receptor regulation in animal models of human disease will provide a more complete understanding of basal ganglia circuitry in health and disease and allow the rational development of pharmacotherapies for these illnesses using drugs selective for the various receptor subtypes.