RECEPTOR MECHANISMS IN MOVEMENT DISORDER PATHOPHYSIOLOGY

基底节在控制正常的运动和运动中起主要作用 协调。基底节的损害导致运动障碍 从严重的运动迟缓、僵硬和震颤到肌张力障碍、舞蹈症和 芭蕾舞剧。某一特定个体或疾病的症状学 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是人体的神经递质 大多数纹状体、苍白球和黑质神经元为兴奋性神经元 氨基酸(EAA)，如谷氨酸，作为神经递质 皮质和丘脑传出至纹状体、丘脑底核和 黑质神经元是多巴胺的神经递质。 黑质纹状体通路，许多纹状体神经元携带腺苷A2 感受器。在过去的几年里，分子生物学的进步 使许多受体亚型的基因得以克隆。这使得 有可能确定这些新生物的分布和调节 基底节神经元特异性亚型的克隆及其受体亚型的研究 它们在运动障碍的病理生理学中的作用。 该计划项目建议书是一个协作性、多中心 新克隆受体亚型在动物体内作用的研究进展 运动障碍的模型。 项目1将确定兴奋性氨基酸受体是否 优先定位于亨廷顿氏变性的神经元 疾病和氨基酸受体基因的表达如何变化 运动障碍的动物模型。项目2将研究该地点 纹状体、皮质和苍白球的多巴胺受体亚型。 项目3将研究腺苷A2受体在 动物和人的分子水平及其受体在动物中的作用 运动障碍的模型。项目4将研究以下因素： 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 亨廷顿病和帕金森病的发病机制 导致缓慢的兴奋性毒性神经元变性。这些项目将 得到行政管理、抗体生产和动物手术的支持 核心。阐明动物体内受体调控的细节 人类疾病的模型将提供一个更完整的理解 基底神经节回路在健康与疾病中的理性化 利用药物治疗这些疾病的药物疗法的发展 对各种受体亚型有选择性。

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.