Synergistic Neuroprotective Mechanisms of Coffee Components in Parkinson's Diseas

咖啡成分对帕金森病的协同神经保护机制

基本信息

批准号：
8734228
负责人：
M. Maral Mouradian
金额：
$ 42.9万
依托单位：
RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-30 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8734228
关键词：
Acute Address Adenosine A2A Receptor Age-Months Anti-Inflammatory Agents Anti-inflammatory Apoptosis Attenuated Biochemical Biochemistry Brain Caffeine Cells Charge Chronic Coffee Complex Consumption Cyclic AMP-Dependent Protein Kinases Data Defect Development Dietary Supplementation Diffuse Drosophila genus Epidemiologic Studies Epidemiology Event Exposure to Goals Human In Vitro Link Lipids Mediating Methylation Mitochondria Modeling Modification Molecular Mus Neurodegenerative Disorders Neurons Oxidation-Reduction Oxidative Stress Parkinson Disease Pathology Patients Pharmacologic Substance Phosphoric Monoester Hydrolases Phosphorylation Play Prevalence Protein phosphatase Proteins Receptor Signaling Regulation Reporting Research Risk Rodent Model Role Signal Transduction Source Testing Toxin Transgenic Mice Work base brain cell cell type cost dietary supplements disability disorder risk dopaminergic neuron efficacy testing in vivo inhibitor/antagonist killings medical food methyl group motor function improvement mouse model neuroprotection overexpression pre-clinical prevent protective effect protein phosphatase methylesterase-1 research study stem success synuclein synucleinopathy

项目摘要

DESCRIPTION (provided by applicant): Coffee is by far the most widely and highly consumed herbal extract. Numerous epidemiological studies indicate that coffee consumption affords reduced risk of Parkinson's disease (PD). This association has been attributed to caffeine, but coffee is much more than just caffeine and the finding that caffeine may be neuroprotective in no way obviates the possibility that other components in coffee may play a synergistic role with caffeine. We have recently isolated a lipid-like component of coffee, EHT, and found it to have a protective effect in mouse models of PD. Biochemical and neuropathological analyses demonstrate that dietary supplementation with EHT leads to decreased ?-synuclein phosphorylation and aggregation, a robust anti-inflammatory effect, and protection against oxidative stress. Studies indicate that the actions of caffeine stem from its antagonism of adenosine A2A receptor signaling, but downstream neuroprotective mechanisms remain to be established. The proposed research will elucidate the molecular mechanisms of neuroprotection mediated by caffeine and EHT as well as their synergy through in vitro biochemical analyses, cell based molecular experiments and in vivo studies in mouse models of PD. The ultimate goal of this work is to develop a dietary supplement(s) or medical food that would slow the progression or prevent the development of neurodegenerative disorders such as PD.

描述（由申请人提供）：咖啡是迄今为止最广泛、消费最多的草药提取物。大量流行病学研究表明，饮用咖啡可以降低患帕金森病 (PD) 的风险。这种关联归因于咖啡因，但咖啡不仅仅是咖啡因，咖啡因可能具有神经保护作用的发现决不能排除咖啡中其他成分可能与咖啡因发挥协同作用的可能性。我们最近从咖啡中分离出一种脂质样成分 EHT，并发现它对 PD 小鼠模型具有保护作用。生化和神经病理学分析表明，饮食中补充 EHT 可降低 β-突触核蛋白磷酸化和聚集，产生强大的抗炎作用，并防止氧化应激。研究表明咖啡因的作用源于其对腺苷 A2A 受体信号传导的拮抗作用，但下游神经保护机制仍有待建立。拟议的研究将通过体外生化分析、基于细胞的分子实验和PD小鼠模型的体内研究，阐明咖啡因和EHT介导的神经保护的分子机制以及它们的协同作用。这项工作的最终目标是开发一种膳食补充剂或医疗食品，以减缓帕金森病等神经退行性疾病的进展或预防其发展。