Role of ABHD6 in 2-AG Signaling

ABHD6 在 2-AG 信号传导中的作用

基本信息

批准号：
9113530
负责人：
Nephi Stella
金额：
$ 34.41万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9113530
关键词：
2-arachidonylglycerol ABHD6 gene Adverse effects Agonist Antiepileptic Agents Attenuated Biochemical Biological Process Brain CNR1 gene Cannabinoids Characteristics Collaborations Coupled Development Drug Kinetics Endocannabinoids Enzymes Epilepsy Exhibits Funding Generations Genetic Goals Grant Health Hippocampus (Brain)Huntington Disease Hydrolysis Incidence Injection of therapeutic agent Knock-in Mouse Laboratory Study Maps Measures Modeling Molecular Monoacylglycerol Lipases Mus Neuroglia Neurons Pathogenesis Patients Pentylenetetrazole Play Process Property Proteomics Regimen Research Role Seizures Signal Transduction Status Epilepticus System Technology Testing Therapeutic Time Tonic - clonic seizures Validation anandamide base cannabinoid receptor early onset endocannabinoid signaling fatty acid amide hydrolase genetic approach in vivo inhibitor/antagonist kainate mouse model nervous system disorder neuropathology novel novel therapeutics presynaptic prevent small hairpin RNA spatiotemporal tool

2-arachidonylglycerol ABHD6 gene Adverse effects Agonist Antiepileptic Agents Attenuated Biochemical Biological Process Brain CNR1 gene Cannabinoids Characteristics Collaborations Coupled Development Drug Kinetics Endocannabinoids Enzymes Epilepsy Exhibits Funding Generations Genetic Goals Grant Health Hippocampus (Brain)Huntington Disease Hydrolysis Incidence Injection of therapeutic agent Knock-in Mouse Laboratory Study Maps Measures Modeling Molecular Monoacylglycerol Lipases Mus Neuroglia Neurons Pathogenesis Patients Pentylenetetrazole Play Process Property Proteomics Regimen Research Role Seizures Signal Transduction Status Epilepticus System Technology Testing Therapeutic Time Tonic - clonic seizures Validation anandamide base cannabinoid receptor early onset endocannabinoid signaling fatty acid amide hydrolase genetic approach in vivo inhibitor/antagonist kainate mouse model nervous system disorder neuropathology novel novel therapeutics presynaptic prevent small hairpin RNA spatiotemporal tool

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项目摘要

DESCRIPTION (provided by applicant): Compounds that target endocannabinoid (eCB) signaling in the brain represent powerful pharmacological tools to probe the basic biological function of this signaling system in healthy and diseased brain and may represent novel therapeutic venues to treat neurological diseases such as Huntington's disease (HD). During the funding cycle of this RO1, our laboratory studied the function of ABHD6 in neurons and glia, as well as the therapeutic potential of ABHD6 inhibitors in R6/2 mice, an early-onset mouse model of HD. We leveraged functional proteomics and shRNA technology and identified ABHD6 as a candidate enzyme for 2-AG hydrolysis in brain. We then developed new ABHD6 inhibitors and showed that ABHD6 activity tightly controls the levels and efficacy of 2-AG at cannabinoid receptors. Together, these studies demonstrated that ABHD6 belongs to the eCB signaling system. Recently we found that in vivo ABHD6 inhibition greatly reduces seizure incidence and attenuates hippocampal neuropathology in R6/2 mice. In this grant, we will test the following hypothesis: The novel enzyme, ABHD6, controls both the level and efficacy of 2-arachidonoylglycerol (2-AG) at cannabinoid CB1 receptors. ABHD6 inhibitors reduce seizure activity in two HD mouse models (R6/2 and HDQ200) and may represent a novel class of therapeutics to treat seizures in general. To test this hypothesis, we propose 3 Aims: AIM 1: Development, validation, and mechanism of action of 3rd generation ABHD6 inhibitors that exhibit superior in vivo selectivity and efficacy. AIM 2: Determine to what extent ABHD6 in vivo inhibition and genetic deletion reduces seizure incidence in HD and chemically-induced seizures mouse models. AIM 3: Why do HD mice seize, and how does ABHD6 prevent this process? Thus we will characterize newly optimized inhibitors of ABHD6, an eCB-hydrolyzing enzyme that we identified during the previous funding period. Coupled to genetic approaches, we will use ABHD6 inhibitors to determine the molecular and cellular details of how this enzyme controls seizure incidence in HD mice models. Completion of the studies outlined above will provide a comprehensive understanding of the role of ABHD6 in healthy and HD mouse brain within the context of epileptic activity. Our long-term goal is to increase our understanding of th role played by ABHD6 in healthy and diseased brain, and help develop novel therapeutics that lack the potential for abuse and adverse effects produced by classic cannabinoid agonists.

描述（由申请人提供）：大脑中靶向内源性大麻素（ECB）信号传导的化合物代表了强大的药理学工具，可探测该信号系统在健康和患病的大脑中的基本生物学功能，并且可能代表治疗神经系统疾病的新型治疗场所，例如亨廷顿氏病（HD）。在此RO1的融资周期中，我们的实验室研究了ABHD6在神经元和神经胶质中的功能，以及在R6/2小鼠中ABHD6抑制剂的治疗潜力，R6/2小鼠是HD的早期发作小鼠模型。我们利用功能性蛋白质组学和shRNA技术，并确定ABHD6是大脑中2 AG水解的候选酶。然后，我们开发了新的ABHD6抑制剂，并表明ABHD6活性紧紧控制了在大麻素受体下2-AG的水平和功效。总之，这些研究表明ABHD6属于欧洲央行信号系统。最近，我们发现体内ABHD6抑制大大降低了癫痫发作的发生率，并减轻了R6/2小鼠的海马神经病理学。在该赠款中，我们将检验以下假设：新型酶ABHD6控制大麻素CB1受体上2-芳基酮甘油（2-AG）的水平和功效。 ABHD6抑制剂减少了两种HD小鼠模型（R6/2和HDQ200）中的癫痫发作活性，并且可能代表了一类新型的治疗疗法，以治疗癫痫发作。为了检验这一假设，我们提出了3个目标：目标1：第三代ABHD6抑制剂的开发，验证和作用机理，在体内选择性和有效性中表现出优异。 AIM 2：确定体内抑制和遗传缺失的ABHD6在多大程度上降低了HD和化学诱导的癫痫发作小鼠模型的癫痫发作。目标3：为什么高清小鼠抓住了，ABHD6如何阻止此过程？因此，我们将表征ABHD6的新优化抑制剂，ABHD6是一种欧洲央行 - 溶解酶，我们在上一个融资期间确定。结合遗传方法，我们将使用ABHD6抑制剂来确定该酶如何控制HD小鼠模型中癫痫发作的分子和细胞细节。上面概述的研究的完成将为ABHD6在癫痫活性的背景下的健康和HD小鼠脑中的作用提供全面的了解。我们的长期目标是提高我们对ABHD6在健康和患病的大脑中所扮演的角色的理解，并有助于开发新的治疗剂，这些治疗剂缺乏经典大麻素激动剂产生的滥用和不良影响的潜力。