Oxysterols and NMDAR Function

描述(由申请人提供)：目前的精神科药物治疗方案仍有许多不足之处，通过正性和负性调节器操纵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的、非常有效的、潜在的内源性NMDARs正向调节剂。该原型是大脑中主要的胆固醇代谢物，24S-羟基胆固醇(24OH)。氧化甾醇和24OH一样，是由胆固醇氧化产生的细胞脂质。流行的观点认为，24OH被合成为一种方便的废物处理工具，用于大脑中翻转的神经元胆固醇池，但我们已经发现，24OH调节NMDAR功能的浓度远远低于在大脑中测得的浓度。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和一种合成类似物Org-1在NMDAR上具有不寻常的增强作用，而另一种胆固醇代谢物25-羟基胆固醇可以拮抗这种作用。我们推测，24OH通过一个新的受体结合部位直接影响NMDAR通道的门控。为了了解氧固醇神经调节的机制，我们与道格拉斯·柯维领导的合成化学实验室开展了长期的跨学科合作。我们建议使用新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固醇作用的亚细胞结构域，并深入了解氧固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增强了突触的可塑性和认知。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性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。在这些研究完成后，我们希望能够阐明一种具有广泛重要性的新型神经调节剂的机制和作用。

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.