Kynurenine metabolites and depression: An in vitro and ex vivo study

犬尿氨酸代谢与抑郁症：一项体外和离体研究

• 批准号: 9112097
• 负责人: Aimin Liu
• 金额: $ 19.77万
• 依托单位: UNIVERSITY OF TEXAS SAN ANTONIO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-11 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9112097
• 关键词: AIDS Dementia Complex; Acids; Affect; Agonist; Alzheimer' s Disease; Amino Acids; Anabolism; Anxiety; Behavior; Biochemistry; Biological Assay; Biological Markers; Brain; Carboxy-Lyases; Cerebrospinal Fluid; Chronic; Clinical; Complex; Correlation Studies; Detection; Development; Diagnostic Procedure; Dioxygenases; Disease; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Epilepsy; Essential Amino Acids; Exhibits; Genes; Glutamates; Goals; Human; Huntington Disease; In Vitro; Inflammation; Inflammatory; Interferon-alpha; Kynurenic Acid; Kynurenine; Label; Lead; Link; Lipid Peroxidation; Liquid substance; Machine Learning; Major Depressive Disorder; Maps; Mental Depression; Metabolic; Metabolic Control; Metabolism; Molecular; Mus; N-Methyl-D-Aspartate Receptors; Neurons; Neurotoxins; Neurotransmitters; Oxidoreductase; Pathway interactions; Patients; Phase; Physicians; Picolinic Acids; Plasma; Positioning Attribute; Production; Proteins; Protocols documentation; Quinolinic Acid; Reaction; Records; Regulation; Research; Research Personnel; Route; Sampling; Scheme; Scientist; Side; Solid; Source; Structure; Testing; Tissues; Tryptophan; Tryptophan 2,3 Dioxygenase; analytical method; base; chemical reaction; cost; cost effective; cytokine; depressive symptoms; design; enzyme mechanism; enzyme pathway; improved; innovation; interest; metabolic profile; neuroinflammation; neuropsychiatric disorder; neurotransmission; novel; patient population; small molecule; small molecule inhibitor; stem; three dimensional structure

 DESCRIPTION (provided by applicant): The kynurenine catabolic pathway for tryptophan degradation in humans produces metabolites that are neurologically active and affect neurotransmission and neuronal integrity. Quinolinic acid (QUIN) is a product of the pathway which has been implicated in numerous neuropsychiatric disorders and has been correlated with depression in patients administered the inflammatory cytokine, interferon (IFN)-α. Besides, activation of the kynurenine pathway by inflammation leads to elevated levels of QUIN, which have been shown to cause depressive-like behavior in mice. The mechanism by which QUIN acts in the brain is to activate excitotoxic neurotransmitter pathways involving the amino acid glutamate and by leading to lipid peroxidation. Following metabolism by indoleamine 2,3-dioxygenase and subsequent steps, three consecutive enzymes of the kynurenine pathway determine the metabolic partitioning of tryptophan metabolites to QUIN, picolinic acid (PIC), or further metabolism. We hypothesize that the shift of QUIN and PIC levels is linked to chronic inflammation and major depression. To test this hypothesis, we will, in the first aim, study the structure and action of the enzymes and the mechanisms controlling QUIN and PIC production. In the second aim, a new, rapid and efficient analytical method will be developed for in vitro and ex vivo quantitation of QUIN and PIC levels and will be applied to samples obtained from patient populations expected to exhibit high levels of QUIN as a result of increased inflammation and from assays using purified protein to simulate similar distributions. Through these studies, the correlation between kynurenine metabolites and major depression will be investigated, and small molecule inhibitors will be used as probes for modulating the production of QUIN and PIC levels.

 描述（由申请人提供）：人类色氨酸降解的犬尿氨酸分解代谢途径产生具有神经活性并影响神经传递和神经元完整性的代谢物。喹啉酸 (QUIN) 是该途径的产物，该途径与许多神经精神疾病有关，并且与服用炎症细胞因子干扰素 (IFN)-α 的患者的抑郁症相关。此外，炎症激活犬尿氨酸通路会导致 QUIN 水平升高，这已被证明会导致小鼠出现抑郁样行为。 QUIN 在大脑中的作用机制是激活涉及氨基酸谷氨酸的兴奋性毒性神经递质途径并导致脂质过氧化。经过吲哚胺 2,3-双加氧酶和后续步骤的代谢后，犬尿氨酸途径的三个连续酶决定色氨酸代谢物向 QUIN、吡啶甲酸 (PIC) 的代谢分配或进一步代谢。我们假设 QUIN 和 PIC 水平的变化与慢性炎症和重度抑郁症有关。为了检验这一假设，我们的首要目标是研究酶的结构和作用以及控制 QUIN 和 PIC 产生的机制。第二个目标是开发一种新的、快速且有效的分析方法，用于 QUIN 和 PIC 水平的体外和离体定量，并将应用于从预计因炎症增加而表现出高水平 QUIN 的患者群体中获得的样本，以及使用纯化蛋白模拟类似分布的测定。通过这些研究，将研究犬尿氨酸代谢物与重度抑郁症之间的相关性，并将使用小分子抑制剂作为调节 QUIN 和 PIC 水平产生的探针。