Opioid Receptor Polymorphism & PD Drug Response

阿片受体多态性

• 批准号: 6634317
• 负责人: LEI YU
• 金额: $ 33.71万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-01 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6634317
• 关键词: Parkinson's disease; Xenopus; brain disorder chemotherapy; genetic polymorphism; genetic promoter element; human subject; human therapy evaluation; levodopa; molecular cloning; opioid receptor; patient oriented research; pharmacogenetics; receptor binding; receptor expression

DESCRIPTION: (Verbatim from the Applicant's Abstract) Parkinson's disease (PD) is a common movement disorder with tremor, rigidity, and bradykinesia. The central event in PD is the loss of the dopaminergic inputs to the basal ganglia. The disease is characterized by great variability from patient to patient in the course of the disease, the relative predominance of various symptoms, the response to L-DOPA therapy, and the development of dyskinesias during L-DOPA therapy. Studies exploring the ramifications of the dopamine deficiency in PD have provided increasing evidence that changes in the other basal ganglia neurotransmitter systems, in particular the opioid system, may also play a role in the disease process. This evidence includes PET scan studies in PD patients that showed correlations between dyskinesias and altered opioid binding levels, as well as work in animal models sugggesting the involvement of opioid system in the development of dyskinesias during L-DOPA therapy. In this revised application, the basic hypothesis we propose to test is that some of the observed variability in PD patient's symptoms and response to L-DOPA may be related to an underlying genetic variation in opioid receptors. We propose to study genetic polymorphism of the mu opioid receptor in PD patients, and to characterize at a cellular level the consequences of these polymorphisms on receptor expression level and receptor function. The specific aims of the proposal are: 1. To identify genetic polymorphisms in both the promoter and the coding region of the mu opioid receptor in PD patients and to determine whether any of the polymorphisms are associated with variations in clinical symptoms and outcomes: 2.) To determine the effect of the coding region polymorphisms on both ligand binding properties of the receptor and receptor-mediated cellular functions; and 3.) To determine the effect of promoter sequence polymorphisms on the expression levels of the receptor. Such functional studies are essential in moving from association to causality. Our preliminary studies of 26 PD patients have identified a mu opioid receptor polymorphism in the PD population. This polymorphism was significantly associated with the clinical outcome of L-DOPA therapy-induced dyskinesia. Further studies in a larger PD patient cohort may identify additional polymorphisms of interest, and may provide predictor for clinical management of PD.

描述：（逐字摘自申请人摘要）帕金森病（PD） 是一种常见的运动障碍，伴有震颤、僵硬和运动迟缓。的 PD中的中心事件是多巴胺能输入到基底神经元的损失， 神经节这种疾病的特点是从病人到病人有很大的变异性。 患者在病程中，各种疾病的相对优势 症状，对左旋多巴治疗的反应，以及运动障碍的发展 在左旋多巴治疗期间研究探索多巴胺的分支 PD的缺乏提供了越来越多的证据表明，其他方面的变化 基底神经节神经递质系统，特别是阿片样物质系统，可以 也在疾病过程中发挥作用。这些证据包括PET扫描 在PD患者中进行的研究显示，运动障碍与改变的 阿片类药物结合水平，以及在动物模型中的工作， 阿片系统参与左旋多巴引起的运动障碍 疗法 在这个修改后的应用程序中，我们提出要测试的基本假设是， 观察到的PD患者症状和对 左旋多巴可能与阿片受体的潜在遗传变异有关。 我们建议研究帕金森病中μ阿片受体的遗传多态性 患者，并在细胞水平上表征这些结果， 多态性对受体表达水平和受体功能的影响。具体 建议的目的是：为了确定两种基因的遗传多态性， 启动子和μ阿片受体的编码区，以及 确定是否有任何多态性与 临床症状和结果：2.）要确定编码的效果， 区域多态性对受体的配体结合特性和 受体介导的细胞功能;和3.）以确定影响 启动子序列多态性对受体表达水平的影响。等 功能研究是从关联转向因果关系的关键。 我们对26名PD患者的初步研究已经确定了一种μ阿片受体， PD人群中的多态性。这种多态性显著 与左旋多巴治疗诱导的运动障碍的临床结果相关。 在更大的PD患者队列中进行的进一步研究可能会发现其他 多态性，并可提供用于临床管理的预测因子 警局