Oxysterols and NMDAR Function

氧甾醇和 NMDAR 功能

基本信息

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
项目类别：
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

项目摘要

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）：当前的精神病药物治疗方案还有很多不足之处，并且通过正和负调节剂对N-甲基-D-天冬氨酸受体（NMDAR）操纵，对包括精神分裂症和抑郁症在内的主要精神病患者具有治疗益处。我们建议利用我们最近发现的NMDAR的新颖，非常有效且潜在的内源性阳性调节剂。该原型是大脑中主要的胆固醇代谢物，24S-羟基胆固醇（24OH）。诸如24OH之类的氧化酚是由胆固醇氧化产生的细胞脂质。流行视图表明24OH被合成为胆固醇神经元池的方便废物处理车，但我们发现24OH在浓度低于大脑中的浓度下调节NMDAR功能。我们将利用创新的化学生物学和生理方法来理解24OH的机制。我们的初步数据表明，24OH和一个合成类似物ORG-1在NMDAR中具有异常增强的作用，而NMDAR与另一种胆固醇代谢物（25-羟基胆固醇）对抗。我们假设24OH通过新型受体结合位点对NMDAR通道门控具有直接影响。为了了解氧蛋白酶神经调节的机制，我们利用了由道格拉斯·科维（Douglas Covey）执导的合成化学实验室的长期跨学科合作。我们建议使用新型的化学标记策略来为细胞生物学和生理研究创建类似物。这些方法将洞悉外源氧蛋白酶作用的亚细胞结构，并洞悉氧蛋白酶作用的特殊动力学。我们还将研究24OH和ORG-1对野生型小鼠突触可塑性和行为的影响，以及在产生24OH的酶中缺乏的小鼠中的影响。初步数据表明24OH和ORG-1增强了突触可塑性和认知。 Weill Cornell医学院的合作者在不同的实验条件下，内源性24OH和ORG-1水平的测量将得到补充。我们拥有强大的跨学科往绩，这将促进快速进步。这些研究完成后，我们期望具有广泛重要性的新型神经调节剂的机制和影响。