Oxysterols and NMDAR Function

氧甾醇和 NMDAR 功能

• 批准号: 8693215
• 负责人: STEVEN J MENNERICK
• 金额: $ 39.78万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-21 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8693215
• 关键词: 25-hydroxycholesterol; Accounting; Adult; Affect; Behavior; Behavioral; Binding Sites; Bioavailable; Biological; Biology; Brain; CYP46A1 gene; Cell membrane; Cells; Cellular biology; Chemicals; Chemistry; Cholesterol; Clinical; Cognition; Cognitive; Collaborations; Complement; Data; Disease; Enzymes; Fostering; Heart Diseases; Hippocampus (Brain); Histocompatibility Testing; Hydroxycholesterols; Image; Ketamine; Kinetics; Laboratories; Lead; Learning; Left; Life; Lipids; Lung diseases; Measurement; Measures; Mediating; Mental Depression; Mental disorders; Mus; N-Methyl-D-Aspartate Receptors; Nervous System Physiology; Neuromodulator; Neurons; Pharmacotherapy; Physiological; Physiology; Positioning Attribute; Property; Refuse Disposal; Rodent; Role; Schizophrenia; Signal Transduction; Site; Slice; Sterols; Stimulus; Structure; Synapses; Synaptic Transmission; Synaptic plasticity; Synthesis Chemistry; System; Testing; Therapeutic; Tissues; Wild Type Mouse; Work; analog; autocrine; cholesterol 24-hydroxylase; drug development; improved; innovation; insight; interdisciplinary collaboration; interest; knockout animal; medical schools; neuropsychiatry; neuroregulation; neurosteroids; novel; oxidation; paracrine; postsynaptic; prototype; public health relevance; receptor; receptor binding; receptor function; transmission process; treatment strategy; wasting

DESCRIPTION (provided by applicant): Current psychiatric pharmacotherapy options leave much to be desired, and manipulation of N-methyl-D-aspartate receptors (NMDARs) by positive and negative regulators has therapeutic benefit in major psychiatric disorders including schizophrenia and depression. We propose to capitalize on our recent discovery of a novel, very potent, and potentially endogenous positive modulator of NMDARs. The prototype is the major cholesterol metabolite in brain, 24S-hydroxycholesterol (24OH). Oxysterols like 24OH are cellular lipids generated from oxidation of cholesterol. Prevailing views suggest 24OH is synthesized as a convenient waste disposal vehicle for the neuronal pool of cholesterol that turns over in brain, but we have discovered that 24OH modulates NMDAR function at concentrations well below those measured in brain. We will leverage innovative chemical biology and physiological approaches toward understanding the mechanisms of 24OH. Our preliminary data suggest that 24OH and a synthetic analogue, Org-1, have unusual potentiating actions at NMDARs that are antagonized by another cholesterol metabolite, 25-hydroxycholesterol. We hypothesize that 24OH has direct effects on NMDAR channel gating through a novel receptor binding site. To understand mechanisms of oxysterol neuromodulation, we exploit a longstanding interdisciplinary collaboration with a synthetic chemistry laboratory, directed by Douglas Covey. We propose to use novel chemical tagging strategies to create analogues for cell biological and physiological studies. These approaches will yield insight into subcellular domains of exogenous oxysterol actions and insight into the peculiar kinetics of oxysterol action. We will also investigate the effects of 24OH and Org-1 on synaptic plasticity and behavior in wild type mice and in mice deficient in the enzyme that produces 24OH. Preliminary data suggest that 24OH and Org-1 enhance synaptic plasticity and cognition. This work will be complemented by measurements of endogenous 24OH and Org-1 levels under varied experimental conditions by collaborators at Weill Cornell Medical College. We have a strong interdisciplinary track record that will foster rapid progress. Upon completion of these studies, we expect to have elucidated mechanisms and effects of a novel neuromodulator with broad importance.

描述（由申请人提供）：目前的精神科药物治疗选择还有很多不足之处，通过正向和负向调节剂操纵 N-甲基-D-天冬氨酸受体 (NMDAR) 对包括精神分裂症和抑郁症在内的主要精神疾病具有治疗益处。我们建议利用我们最近发现的一种新型、非常有效、潜在的内源性 NMDAR 正调节剂。原型是大脑中的主要胆固醇代谢物，24S-羟基胆固醇（24OH）。 24OH 等氧甾醇是胆固醇氧化产生的细胞脂质。普遍观点认为 24​​OH 是作为大脑中胆固醇神经元库的便捷废物处理工具而合成的，但我们发现 24OH 在远低于大脑中测量值的浓度下调节 NMDAR 功能。我们将利用创新的化学生物学和生理学方法来了解 24OH 的机制。我们的初步数据表明，24OH 和合成类似物 Org-1 对 NMDAR 具有不同寻常的增强作用，而 NMDAR 会被另一种胆固醇代谢物 25-羟基胆固醇拮抗。我们假设 24OH 通过新的受体结合位点对 NMDAR 通道门控有直接影响。为了了解氧固醇神经调节的机制，我们利用与道格拉斯·柯维 (Douglas Covey) 领导的合成化学实验室的长期跨学科合作。我们建议使用新颖的化学标记策略来创建用于细胞生物学和生理学研究的类似物。这些方法将深入了解外源性氧甾醇作用的亚细胞域，并深入了解氧甾醇作用的特殊动力学。我们还将研究 24OH 和 Org-1 对野生型小鼠和缺乏产生 24OH 的酶的小鼠突触可塑性和行为的影响。初步数据表明 24OH 和 Org-1 增强突触可塑性和认知。威尔康奈尔医学院的合作者将在不同的实验条件下测量内源 24OH 和 Org-1 水平，以补充这项工作。我们拥有强大的跨学科记录，这将促进快速进步。完成这些研究后，我们期望阐明具有广泛重要性的新型神经调节剂的机制和作用。