PRESYNAPTIC NEUROCHEMICAL MARKERS

突触前神经化学标志物

• 批准号: 6267438
• 负责人: KIRK A. FREY
• 金额: $ 18.57万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-01 至 1999-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6267438
• 关键词: Alzheimer's disease; Huntington's disease; Parkinson's disease; acetylcholine; acetylcholinesterase; autoradiography; biomarker; choline; dietary supplements; dopamine; experimental brain lesion; human tissue; laboratory rat; membrane transport proteins; muscarinic receptor; neural transmission; neuroanatomy; neurochemistry; neuropharmacology; neurotransmitter transport; nutrition related tag; postmortem; progressive supranuclear palsy; receptor binding; synaptic vesicles

The experiments proposed in this project will elucidate important relationships between ligand binding site markers of cholinergic or dopaminergic neurons and the integrity and density of their terminals in the brain. We will seek to distinguish those markers that respond dynamically to perturbations in synaptic activity from markers whose expression appears related only to the survival of intact presynaptic nerve endings. The former may be of utility in elucidating regulatory responses to disease or following treatment, but will not serve as reliable quantitative markers of neuronal density. Markers satisfying the latter criterion are well-suited to the prospective analysis of disease and therapeutic interventions in neurodegenerative disorders, potentially providing objective measures of progression or response. The capability to determine such markers in noninvasive clinical settings, with the use of emission tomographic imaging, may ultimately permit detailed analyses of neuronal survival and death not previously possible. Our hypotheses are focused on the study of radioligand binding sites located on the membranes of synaptic vesicles, specific to cholinergic or to monoaminergic neurons. The ligands [3H]vesamicol and [3H]methoxytetrabenazine will be applied to the evaluation of these neuronal populations, respectively. We will compare the neurobiologic expression and regulation of these binding sites with additional measures of cell membrane transport sites for the presynaptic uptake of choline or of dopamine. Regulatory changes in the activities of these latter sites are well-known in the case of cholinergic neurons, and are potentially present in dopaminergic nerve terminals as well. Our experimental design will involve the use of chronic drug administration in animals to produce alterations in synaptic activity by potentiating or inhibiting neurotransmission. Under these conditions, regulatory modulation in neurotransmitter numbers are known to occur, permitting parallel documentation of the altered state of synaptic activity. We will then determine the possible presence of changes in the synaptic vesicle and presynaptic membrane uptake sites. Comparison of the above results of drug challenges and those following selective brain lesions, resulting in cortical cholinergic deficits or in striatal dopaminergic deficits, will be make with ligand binding markers in postmortem brain samples from subjects with Alzheimers's and Parkinson's diseases. Combined, these results will enhance understanding of the relateive contributions of neuronal loss and of secondary regulatory responses in these idiopathic disorders. Future clinical research studies, based on carefully-chosen markers of synaptic integrity, will then be possible.

在这个项目中提出的实验将阐明 配体结合位点标记之间的重要关系 胆碱能或多巴胺能神经元的完整性 和它们在大脑中的终端密度。 我们将寻求 来区分那些动态响应于 来自标记物的突触活动的扰动， 表达似乎只与完整的 突触前神经末梢 前者可能是有用的， 阐明对疾病的调节反应或以下 治疗，但不会作为可靠的定量 神经元密度的标志物。 满足后者的标记 标准非常适合于前瞻性分析， 神经退行性疾病和治疗干预 疾病，可能提供客观的措施， 进展或反应。 确定这种能力 在非侵入性临床环境中的标记物， 发射断层成像，最终可能允许 神经元存活和死亡的详细分析， 以前可能的。 我们的假设集中在放射性配体的研究 位于突触膜上的结合位点 胆碱能或单胺能特异性囊泡 神经元 配体[3H]vesamicol和 [3H]甲氧基丁苯那嗪将用于评价 这些神经元的数量。 我们将 比较神经生物学表达和调节， 这些结合位点与额外的细胞测量 突触前摄取的膜转运位点 胆碱或多巴胺。 的监管变化 这些网站的活动是众所周知的情况下， 胆碱能神经元，并可能存在于 多巴胺能神经末梢也一样。 我们的实验 设计将涉及使用慢性药物管理 在动物中产生突触活动的改变， 增强或抑制神经传递。 根据这些 条件，神经递质调节 已知会发生数字， 记录突触活动状态的改变。 然后我们将确定可能存在的变化， 突触囊泡和突触前膜摄取位点。 上述药物挑战结果的比较， 选择性脑损伤后，导致 皮质胆碱能缺陷或纹状体多巴胺能 缺陷，将与配体结合标志物， 阿尔茨海默氏症患者的死后大脑样本 和帕金森氏症。 综合起来，这些结果将 加强对有关贡献的了解 神经元丢失和次级调节反应 这些特发性疾病 未来的临床研究 研究，基于仔细选择的突触标记， 完整性将成为可能。