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.

躁郁症（BD）是一种常见的严重，慢性和威胁生命的疾病；然而，尽管有很多研究，但对于基本的分子神经生物学仍缺乏知识。近年来，情绪障碍的长期治疗可能涉及对关键神经元电路中信号通路和基因表达的战略调节，而微阵列方法论的进步极大地增强了我们识别新型目标的能力，这是对神经药物研究的主要问题，是对治疗性相关性的归因于任何相关性的目标。因此，我们已经实施了一系列验证标准，包括以下内容：（1）与临床治疗作用一致的剂量和时间框架； （2）在结构上高度不同但临床上有效的药物中观察到； （3）针对疾病的脑部区域（4）特定于蛋白质水平验证的疾病（4）。 使用这些严格的标准，我们最近的微阵列研究揭示了对情绪稳定器锂和丙戊酸的长期作用的新目标。以治疗剂量的两种药物的长期给药增加了海马中BAG-1（Bcl-2相关的雌激素）的表达。此外，这些发现在蛋白质水平上得到了验证，并使用类似的严格标准在人类神经母细胞瘤细胞中得到了证实。 Bag-1是Bcl-2的重要伴侣，可以增强Bcl-2！| s抗凋亡功能；此外，通过与RAF的相互作用，Bag-1能够激活ERK MAP激酶。与此一致，我们发现锂和丙戊酸激活ERK MAP激酶并发挥抗凋亡作用。 BAG-1还抑制糖皮质激活，这可能抵消BD中观察到的高皮质血症的有害作用。因此，SH-SY5Y细胞与糖皮质激素反应元件（GRE）和糖皮质激素受体α（GR ??）共转染，并进行了功能研究。我们发现慢性锂（在治疗浓度下）抑制糖皮质激活。时间框架和有效的药物浓度显示出与诱导上调的Bag-1相同的模式。总之，数据表明，BAG-1可能代表了长期治疗双相情感障碍的新型，高度治疗相关的靶标。