IN-VIVO PROBES OF NIGROSTRIATAL CELL DEGENERATION

黑质纹状体细胞变性的体内探针

• 批准号: 2431251
• 负责人: JORGE R BARRIO
• 金额: $ 29.59万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-06-01 至 1999-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2431251
• 关键词: Parkinson's disease; Primates; aromatic L aminoacid decarboxylase; cell death; central neural pathway /tract; corpus striatum; disease /disorder model; dopamine; dopamine receptor; enzyme activity; methylphenyltetrahydropyridine; neural degeneration; neurochemistry; neurotransmitter transport; positron emission tomography; substantia nigra

DESCRIPTION (Investigator's Abstract): The central hypothesis of this work is that radiolabeled enzyme markers of presynaptic dopaminergic function used with positron emission tomography (PET) are not linear indicators of nigrostriatal cell losses. It is expected that axonal sprouting with synapses would respond quickly to early signs of nigrostriatal dopaminergic degeneration as part of the compensatory mechanisms at play to maintain functional activity. If so, substantial changes in aromatic amino acid decarboxylase (AAAD) activities and dopamine reuptake sites are not expected to occur during this adjustment period and, therefore, the AAAD-dependent kinetics and dopamine reuptake ligand binding will not be sensitive to these initial changes. To test this hypothesis, we will use the MPTP-monkey-model of Parkinson's disease (both symptomatic and asymptomatic) to correlate in a controlled environment the graded effects of nigrostriatal cell loss on presynaptic function with the biochemistry and central kinetics of the radiolabeled probes. We will focus our in on the initial stages of cell degeneration, with the aim of providing probes that will detect vestigation neurochemical deficiencies preceding clinical symptoms. We will combine the unique expertise and resources of two leading centers in the world, namely the Parkinson's Institute (Dr. W. Langston, ector) in I methyl-4- phenyl- I ,2,3,6 tetrahydropyridine (MPTP)-exposure to non-humans primates and humans, and UCLA, in functional imaging with positron emission tomography. With a "gold standard" provide-by concomitant cytological and neurochemical information, in-vivo PET data will be correlated with the functional integrity of the dopaminergic system. If this work is successful, we will have developed new in-vivo approaches to: 1) unveil otherwise undetected, early signs of nigrostriatal cell degeneration; 2) trace striatal AAAD activity allowing for evaluation of specific pharmacological interactions (e.g., methamphetamine) and the effects of cell degeneration. The combination of dopamine enzyme probes and, net dopamine re-uptake ligands ("cocaine receptor" ligands), will provide the necessary tools and contribute to the logic necessary for the non-invasive evaluation of the functional activity of central dopaminergic mechanisms in health disease states.

描述（研究者摘要）：本研究的中心假设 工作是突触前多巴胺能的放射性标记酶标记物 正电子发射断层扫描 (PET) 使用的函数不是线性的 黑质纹状体细胞损失的指标。预计轴突 突触的萌芽会对早期迹象做出快速反应 黑质纹状体多巴胺能变性作为代偿性的一部分 维持功能活动的机制。如果是的话，实质性的 芳香族氨基酸脱羧酶（AAAD）活性的变化和 在此调整期间预计不会出现多巴胺再摄取位点 因此，AAAD 依赖性动力学和多巴胺再摄取 配体结合对这些初始变化不敏感。 为了检验这个假设，我们将使用帕金森病的 MPTP 猴子模型 疾病（有症状和无症状）与受控的相关 环境黑质纹状体细胞损失对突触前的分级影响 与放射性标记的生物化学和中心动力学有关的功能 探针。我们将重点关注细胞退化的初始阶段， 目的是提供能够检测调查的探针 神经化学物质缺乏先于临床症状。我们将结合 世界上两个领先中心的独特专业知识和资源， 即帕金森病研究所（W. Langston 博士，主任）在 I 甲基-4- 苯基-I,2,3,6 四氢吡啶 (MPTP)-与非人类接触 灵长类动物和人类，以及加州大学洛杉矶分校，在正电子功能成像中 发射断层扫描。伴随着“黄金标准”提供 细胞学和神经化学信息，体内 PET 数据将 与多巴胺能系统的功能完整性相关。 如果这项工作成功，我们将开发出新的体内 方法： 1) 揭示黑质纹状体细胞未被发现的早期迹象 退化; 2) 追踪纹状体 AAAD 活动，以便评估特定的 药理相互作用 （例如甲基苯丙胺）和细胞变性的影响。 多巴胺酶探针和净多巴胺再摄取的组合 配体（“可卡因受体”配体），将提供必要的工具 并为非侵入性评估提供必要的逻辑 健康中枢多巴胺能机制的功能活动 疾病状态。