Microarray Studies -- Long Term Treatment for Bipolar

微阵列研究——双相情感障碍的长期治疗

• 批准号: 6824378
• 负责人: HUSSEINI K MANJI
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6824378
• 关键词: BCL2 gene /protein; biotechnology; bipolar depression; brain mapping; corticosteroid receptors; drug administration rate /duration; drug interactions; glucocorticoids; hippocampus; hormone regulation /control mechanism; human tissue; lithium; mental disorder chemotherapy; microarray technology; mitogen activated protein kinase; protein quantitation /detection; psychopharmacology; receptor expression; stimulant /agonist; transfection; valproate

Bipolar Disorder (BD) is a common severe, chronic, and life-threatening illness; despite much research, however, there is a dearth of knowledge concerning the underlying molecular neurobiology. It has become increasingly appreciated in recent years that the long term treatment of mood disorders likely involves the strategic regulation of signaling pathways and gene expression in critical neuronal circuits While advances in microarray methodologies have greatly enhanced our ability to identify novel targets, a major problem inherent in neuropharmacologic research is the attribution of therapeutic relevance to any observed biochemical target. We have therefore implemented a series of validating criteria, including the following: (1) dose and time frame consistent with clinical therapeutic effects; (2) observed with structurally highly dissimilar but clinically efficacious agents; (3) specific to brain regions implicated in the disorder (4) specific for mood stabilizers (5) validated at a protein level. Using these stringent criteria, our recent microarray studies have revealed a novel target for the long-term actions of the mood stabilizers lithium and valproate. Chronic administration of both agents at therapeutic doses increased the expression of BAG-1 (bcl-2 associated athanogene) in the hippocampus. Furthermore, these findings were validated at the protein level, and were confirmed in human neuroblastoma cells using similar stringent criteria. Bag-1 is an important chaperone of bcl-2, and enhances bcl-2!|s anti-apoptotic functions; furthermore, through interaction with raf, Bag-1 is able to activate ERK MAP kinases. Consistent with this, we found that lithium and valproate activate ERK MAP kinases and exert anti-apoptotic effects. Bag-1 also inhibits glucocorticoid activation, which may counteract the deleterious effects of hypercortisolemia seen in BD. SH-SY5Y cells were therefore co-transfected with glucocorticoid response element (GRE) and glucocorticoid receptor alpha (GR??) and functional studies were undertaken. We found that chronic lithium (at therapeutic concentrations) inhibits glucocorticoid activation. The time frame and the effective drug concentrations show the same pattern as that induced up-regulated bag-1. Together, the data suggests that Bag-1 may represent a novel, highly therapeutically relevant target in the long-term treatment of bipolar disorder.

双相情感障碍(BD)是一种常见的严重、慢性和危及生命的疾病；然而，尽管有很多研究，但关于其潜在的分子神经生物学方面的知识还很缺乏。近年来，人们越来越认识到，情绪障碍的长期治疗可能涉及对关键神经元回路中信号通路和基因表达的战略性调节，而微阵列方法的进步极大地增强了我们识别新靶点的能力，神经药理学研究中固有的一个主要问题是将治疗相关性归因于任何观察到的生化靶点。因此，我们实施了一系列验证标准，包括：(1)与临床疗效一致的剂量和时间框架；(2)使用结构高度不同但临床有效的药物进行观察；(3)针对与疾病有关的大脑区域；(4)针对情绪稳定剂；(5)在蛋白质水平上进行验证。 使用这些严格的标准，我们最近的微阵列研究揭示了情绪稳定剂锂和丙戊酸盐的长期作用的新靶点。这两种药物在治疗剂量下的慢性给药增加了BAG-1(bcl2相关基因)在海马区的表达。此外，这些发现在蛋白质水平得到了验证，并在人类神经母细胞瘤细胞中得到了证实，使用了类似的严格标准。BAG-1是bcl-2的重要伴侣，可增强bcl-2的抗凋亡功能！|S还可通过与RAF的相互作用激活ERK的丝裂原活化通路。与此一致，我们发现锂和丙戊酸盐激活ERK-MAP激酶，并发挥抗细胞凋亡的作用。BAG-1还抑制糖皮质激素的激活，这可能抵消BD中出现的高皮质醇血症的有害影响。将糖皮质激素反应元件(GRE)和糖皮质激素受体α(GR？？)共转染SH-SY5Y细胞。并进行功能研究。我们发现慢性锂(在治疗浓度下)抑制糖皮质激素的激活。时间框架和有效药物浓度与诱导BAG-1上调的模式相同。总之，这些数据表明，BAG-1可能代表了双相情感障碍长期治疗中一个新的、高度治疗相关的靶点。