FFAR4 and nigrostriatal function: A novel target for treatment of PD?

FFAR4 和黑质纹状体功能：PD 治疗的新靶点？

• 批准号: 9111512
• 负责人: Nader H Moniri
• 金额: $ 7.71万
• 依托单位: MERCER UNIVERSITY MACON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9111512
• 关键词: Agonist; Anabolism; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Behavior; Biological Models; Brain; Brain region; Cell Culture Techniques; Cell Death; Cell Line; Cell membrane; Cell model; Cell surface; Clinical; Cognitive deficits; Corpus striatum structure; Cultured Cells; Data; Degenerative Disorder; Development; Diet; Dietary intake; Disease; Docosahexaenoic Acids; Dopamine; Eicosapentaenoic Acid; Enzymes; Etiology; Fatty Acids; Fatty acid glycerol esters; Functional disorder; Future; G-Protein-Coupled Receptors; Goals; Gold; Hypothalamic structure; Immunofluorescence Immunologic; Laboratories; Lead; Lesion; Mammals; Mediating; Metabolism; Modeling; Motor; Motor Activity; Movement; Nerve; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neurotoxins; Neurotransmitters; Nonesterified Fatty Acids; Omega-3 Fatty Acids; PC12 Cells; Parkinson Disease; Pathway interactions; Pharmacologic Substance; Pharmacotherapy; Pheochromocytoma; Phospholipids; Phosphorylation; Physiological; Pilot Projects; Pituitary Gland; Play; Publishing; Rattus; Regulation; Role; Serine; Signal Transduction; Staging; Surface; Symptoms; System; Testing; Time; Tissues; Tremor; Tyrosine 3-Monooxygenase; Work; alpha-Linolenic Acid; base; diabetic; disturbance in affect; dopaminergic neuron; immunoreactivity; interest; knowledge base; long chain fatty acid; motor disorder; neuron loss; neuroprotection; nigrostriatal pathway; novel; prevent; protective effect; public health relevance; putamen; receptor; saturated fat; standard care

 DESCRIPTION (provided by applicant): Parkinson's disease (PD) is amongst the most prevalent of brain neurodegenerative diseases, and is characterized by movement symptoms including rigidity, tremor, and postural instability. Though an absolute cause of PD has not been discovered, the clinical symptomology evolves due to selective destruction of neurons in the nigrostriatal brain region that are responsible for synthesis of the key neurotransmitter dopamine (DA). Since nigrostriatal neurons regulate coordinated movement in mammals, their destruction as occurs in PD, leads to movement dysfunction. The gold-standard for treatment of PD over the last 4 decades has been administration of the DA precursor L-DOPA, which increases the levels of DA in the nigrostriatal pathway. Importantly, DA synthesis in the brain is regulated by the critical enzyme tyrosine hydroxylase (TH) and as such, approaches that increase TH activity would be expected to increase DA synthesis, and alleviate movement dysfunction. Our laboratory has demonstrated that agonism of the recently discovered free-fatty acid receptor-4 (FFAR4) leads to activation of TH in the rat PC12 cell line that is well-accepted as a model system for neuronal DA synthesis. Additionally, we show that FFAR4 agonism offers significant protection against neurotoxin-mediated cell death in PC12 cells, suggesting that FFAR4 may also have a distinct neuroprotective role. Importantly, FFAR4 is agonized by long-chained saturated fats, including the dietary polyunsaturated omega-3 fatty acids (ω3FA), which have long been known to provide neuroprotective roles in degenerative diseases, including PD. Based on these results, we hypothesize that FFAR4 agonism by ω3FA and synthetic FFAR4 agonists will lead to TH activation and DA synthesis in the rat brain, and may offer neuroprotection in a rat model of PD. This project seeks to test this hypothesis by directly assessing the role of FFAR4 in TH activity and DA synthesis in rat nigrostriatal tissue, and evaluating the neuroprotective role that FFAR4 may play in a rat model of PD. Results of this work will establish a knowledge base towards understanding the physiological role of FFAR4 in nigrostriatal DA neurons and reveal if FFAR4 is a valid physiological target for treatment of PD.

 描述（由申请人提供）：帕金森病（PD）是最常见的脑神经退行性疾病之一，其特征在于运动症状，包括僵硬、震颤和姿势不稳定。虽然尚未发现PD的绝对原因，但由于黑质纹状体脑区负责合成关键神经递质多巴胺（DA）的神经元的选择性破坏，临床病理学发生了变化。由于黑质纹状体神经元调节哺乳动物的协调运动，它们的破坏，如发生在PD，导致运动功能障碍。在过去的40年中，治疗PD的金标准是给予DA前体L-DOPA，其增加黑质纹状体通路中的DA水平。重要的是，大脑中的DA合成受关键酶酪氨酸羟化酶（TH）调节，因此，增加TH活性的方法有望增加DA合成，并缓解运动功能障碍。我们的实验室已经证明，最近发现的游离脂肪酸受体-4（FFAR 4）的激动导致TH在大鼠PC 12细胞系中的激活，该细胞系被广泛接受为神经元DA合成的模型系统。此外，我们表明，FFAR 4激动剂提供了显着的保护对神经毒素介导的细胞死亡的PC 12细胞，这表明FFAR 4也可能有一个独特的神经保护作用。重要的是，FFAR 4受到长链饱和脂肪的刺激，包括膳食多不饱和ω-3脂肪酸（ω3FA），长期以来一直被认为在退行性疾病（包括PD）中提供神经保护作用。基于这些结果，我们假设ω3FA和合成的FFAR 4激动剂的FFAR 4激动将导致大鼠脑中TH激活和DA合成，并且可能在PD大鼠模型中提供神经保护。本项目旨在通过直接评估FFAR 4在大鼠黑质纹状体组织TH活性和DA合成中的作用，并评估FFAR 4在PD大鼠模型中可能发挥的神经保护作用来验证这一假设。这项工作的结果将建立一个知识库，了解黑质纹状体DA神经元中FFAR 4的生理作用，并揭示FFAR 4是否是治疗PD的有效生理靶点。