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，关于潜在的分子神经生物学的知识仍然缺乏。近年来，人们越来越认识到情绪障碍的长期治疗可能涉及关键神经回路中信号通路和基因表达的战略性调节。尽管微阵列方法的进步极大地增强了我们识别新靶点的能力，但神经药理学研究中固有的一个主要问题是治疗与任何观察到的生化靶点的相关性。因此，我们实施了一系列验证标准，包括：(1)剂量和时间框架与临床治疗效果一致；(2)使用结构高度不同但临床有效的药物进行观察；(3)特定于与该障碍有关的大脑区域(4)特定于情绪稳定剂(5)在蛋白质水平上得到验证。