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Endocannabinoid Metabolism and Synaptic Function

内源性大麻素代谢和突触功能

基本信息

批准号：
10322050
负责人：
CHU CHEN
金额：
$ 38.75万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-02-05 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10322050
关键词：
2-arachidonylglycerol 2-arachidonylglycerol signaling 3&apos Untranslated Regions Agonist Anti-Anxiety Agents Antidepressive Agents Behavioral Binding Binding Sites Brain CNR1 gene CNR2 gene Chronic Dendritic Spines Down-Regulation Endocannabinoids Enzymes EphB2 Receptor Epigenetic Process Genetic Genetic Transcription Glutamate Receptor Goals Hippocampus (Brain)Homeostasis Impairment Knockout Mice Knowledge Lead Learning Lentivirus Long-Term Potentiation Mediating Memory Mental disorders Messenger RNA Metabolism MicroRNAs Molecular Monoacylglycerol Lipases Morphology Mus NF-kappa B Neurocognitive Neurologic Performance Peroxisome Proliferator-Activated Receptors Pharmacology Play Porifera Prevention Psyche structure Regulation Research Research Project Grants Role SIRT1 gene Signal Pathway Structure Synapses Synaptic Transmission Synaptic plasticity Synaptophysin System Testing Untranslated RNA Untranslated Regions cognitive function density effective therapy endocannabinoid signaling endogenous cannabinoid system functional plasticity improved knock-down loss of function mental disorder prevention nervous system disorder neural circuit neurocognitive disorder neuropsychiatric disorder overexpression promoter synaptic function treatment strategy

项目摘要

Summary The long-term goal of this research project is to understand cellular, molecular, and epigenetic mechanisms of endocannabinoid (eCB) signaling that may modulate synaptic and neurocognitive functions. While the eCB system is known to play an important role in regulation of brain homeostasis, accumulated information suggests that the eCB system is also involved in several mental and neurological disorders. Augmentation of eCB signaling by inhibition of eCB metabolism has been proposed as a promising therapy for treatment and prevention of mental and neurocognitive illnesses. However, our understanding of the mechanisms underlying augmentation of eCB signaling by chronic inhibition of eCB metabolism in synaptic activity is still limited. Strengthening endocannabinoid 2-arachidonoylglycerol (2-AG) signaling by chronic inactivation of monoacylglycerol lipase (MAGL), the primary enzyme that hydrolyzes 2-AG in the brain, has been shown to produce antidepressant- and anxiolytic-like effects and enhance hippocampal synaptic plasticity as well as learning and memory. Our recent studies showed that sustained inactivation of MAGL increases the density of dendritic spines and expression of glutamate receptor subunits in the hippocampus. This suggests that augmentation of 2-AG signaling by inhibition of MAGL regulates structural and functional plasticity of synapses that determine activity of neural circuits and corresponding neurocognitive functions. MicroRNAs (miRNAs) are small noncoding RNAs that negatively regulate expression and function of target molecules. However, we do not know whether miRNAs that target molecules involved in maintaining the integrity of synaptic structure and function are regulated by eCB signaling. In the proposed studies, we will test the hypothesis that regulation of synaptic activity and cognitive function by chronic inactivation of MAGL is through 2-AG signaling-mediated suppression of the miRNA that targets the molecules important for regulation of synaptic activity. The research proposed in this application is expected to further our understanding of the mechanisms underlying augmentation of eCB signaling in regulation of synaptic and neurocognitive functions, which may lead to future research on improving strategies for the treatment and prevention of mental and neurological illnesses.

概括该研究项目的长期目标是了解细胞、分子和表观遗传机制内源性大麻素 (eCB) 信号传导可调节突触和神经认知功能。虽然欧洲央行众所周知，该系统在调节大脑稳态、积累信息方面发挥着重要作用表明 eCB 系统还与多种精神和神经系统疾病有关。增强通过抑制 eCB 代谢的 eCB 信号传导已被提议作为一种有前途的治疗方法预防精神和神经认知疾病。然而，我们对潜在机制的理解通过长期抑制突触活动中的 eCB 代谢来增强 eCB 信号传导仍然有限。通过长期失活增强内源性大麻素 2-花生四烯酰甘油 (2-AG) 信号传导单酰基甘油脂肪酶 (MAGL) 是大脑中水解 2-AG 的主要酶，已被证明可以产生抗抑郁和抗焦虑样作用，增强海马突触可塑性以及学习和记忆。我们最近的研究表明，MAGL 的持续失活会增加树突棘和海马谷氨酸受体亚基的表达。这表明通过抑制 MAGL 增强 2-AG 信号传导调节突触的结构和功能可塑性决定神经回路的活动和相应的神经认知功能。微小RNA (miRNA) 是负调控靶分子表达和功能的小非编码 RNA。然而，我们做不知道靶向分子的 miRNA 是否参与维持突触结构的完整性和功能受 eCB 信号调节。在拟议的研究中，我们将检验以下假设：监管 MAGL 慢性失活通过 2-AG 信号传导介导突触活动和认知功能抑制针对突触活性调节重要分子的 miRNA。研究本申请中提出的建议有望进一步加深我们对潜在机制的理解增强 eCB 信号在突触和神经认知功能的调节中的作用，这可能会导致未来关于改进精神和神经疾病治疗和预防策略的研究。