PKC SIGNALING AND THE TREATMENT OF BIPOLAR DISORDER

PKC 信号传导和双相情感障碍的治疗

• 批准号: 2702902
• 负责人: HUSSEINI K MANJI
• 金额: $ 14.89万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-01 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2702902
• 关键词: G protein; RNase protection assay; biological signal transduction; bipolar depression; clinical research; enzyme activity; human subject; immunoprecipitation; isozymes; laboratory rat; lithium; lymphocyte; mental disorder diagnosis; microdialysis; nerve /myelin protein; neural growth associated protein; neuroanatomy; neuropharmacology; platelets; protein kinase C; transcription factor; valproate

DESCRIPTION (Adapted from applicant's abstract): BD, manic-depressive illness is a severe, chronic and disabling disorder with a life-time prevalence of 1.2 percent. The discovery of lithium's efficacy as a mood-stabilizing agent revolutionized the treatment of patients with BD, but, despite its role as one of psychiatry's most important treatments the biochemical basis for lithium's antimanic and mood-stabilizing actions remains to be fully elucidated. Elucidation of the mechanism(s) by which lithium stabilizes an underlying dysregulation of limbic and limbic-associated function also offers the potential to delineate the underlying etiology/pathophysiology of BD. A major problem inherent in neuropharmacologic research, however, is the difficulty in attributing therapeutic relevance to any observed biochemical finding. One potential approach to ascribe therapeutic relevance to any biochemical findings is to identify common biochemical targets which are modified by drugs belonging to the same therapeutic class but possessing distinct chemical structures (e.g., lithium and valproic acid (VPA)). A large body of data has shown that lithium exerts major effects on the PKC signaling pathway. Most of the data, however, has been derived from preclinical rodent studies, thereby precluding an adequate understanding of the therapeutic relevance of these biochemical findings. These studies indicate two important and highly clinically relevant directions for future research: first, it is important to determine if similar modulation of the PKC signaling pathway is also brought about by other pharmacological agents with proven efficacy in the treatment of BD such as VPA; and second, it is critical to ultimately elucidate the relationship between these biochemical changes and clinical response, which may lead to the identification of biochemical and/or genetic predictors of outcome. Thus, in this proposal, the investigator's specific aims are to: 1) Characterize the effects of VPA on the PKC signaling pathway in the brain. In order to ascribe potential therapeutic relevance to the biochemical findings, they will be investigated in parallel with lithium: a) in specific brain regions, and b) in a clinically meaningful temporal profile, namely acutely, chronically, following medication withdrawal, and medication re-administration. 2) Determine the relationship between the lithium or VPA-induced changes in the PKC signaling system in rat brain and in rat peripheral cells; ultimately the investigator wishes to determine the relationship between treatment-induced changes in the PKC signaling system and treatment response in BD patients. The demonstration of a relationship between the changes in the CNS and the periphery in rodents will allow for a subsequent investigation in BD patients. This is imperative because, in order to establish therapeutic relevance for any biochemical findings, it is necessary to demonstrate: a) that these biochemical effects do, in fact, occur in patients administered the pharmacological agents in a clinically relevant paradigm; and b) that there is a relationship between the biochemical changes and treatment response. Ultimately, elucidating the mechanisms by which lithium and VPA stabilize mood should improve the prospects for the development of more effective long-term treatments, and for the identification of biochemical predictors of treatment response.

描述（改编自申请人的摘要）：BD，躁狂抑郁症 疾病是一种严重的、慢性的、致残的疾病，会伴随终生 患病率为 1.2%。 锂的功效的发现 情绪稳定剂彻底改变了 BD 患者的治疗， 但是，尽管它是精神病学最重要的治疗方法之一 锂的抗躁狂和情绪稳定作用的生化基础 仍有待充分阐明。 阐明其机制 锂可以稳定边缘系统的潜在失调 边缘相关功能也提供了描绘边缘系统的潜力 BD 的潜在病因学/病理生理学。 固有的一个主要问题是 然而，神经药理学研究的困难在于归因 与任何观察到的生化发现的治疗相关性。 一种潜力 将治疗相关性归因于任何生化结果的方法是 识别被属于以下药物修饰的常见生化靶点 相同的治疗类别但具有不同的化学结构 （例如锂和丙戊酸 (VPA)）。 大量数据表明 锂对 PKC 信号通路有重要影响。 大部分的 然而，数据来自临床前啮齿动物研究，因此 妨碍了对这些治疗相关性的充分理解 生化结果。 这些研究表明两个重要且高度 未来研究的临床相关方向：首先，很重要 以确定 PKC 信号通路的类似调节是否也存在 由其他已被证实有效的药物所引起 BD 的治疗，例如 VPA；其次，至关重要的是最终 阐明这些生化变化与临床之间的关系 反应，这可能导致生化和/或遗传的鉴定 结果的预测因素。 因此，在本提案中，研究者的具体 目的是： 1) 表征 VPA 对 PKC 信号传导的影响 大脑中的通路。 为了归因潜在的治疗相关性 根据生化结果，将同时进行研究 锂：a）在特定的大脑区域，b）在有临床意义的区域 时间分布，即急性、慢性、用药后 停药和重新给药。 2）确定关系 锂或 VPA 引起的 PKC 信号系统变化之间的关系 大鼠大脑和大鼠外周细胞；最终研究者希望 确定治疗引起的 PKC 变化之间的关系 BD 患者的信号系统和治疗反应。 示威活动 中枢神经系统与周围神经系统变化的关系 啮齿动物将允许对 BD 患者进行后续调查。 这是 势在必行，因为为了建立任何治疗的相关性 生化结果，有必要证明： a) 这些 事实上，生化效应确实发生在服用该药物的患者身上。 临床相关范例中的药物制剂； b) 那里 是生化变化和治疗反应之间的关系。 最终，阐明锂和 VPA 稳定的机制 心情要改善，发展前景更有效 长期治疗以及生化预测因子的鉴定 的治疗反应。