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; 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，慢性和残疾疾病，终身 患病率为1.2％。 发现锂的功效是 情绪稳定的药物彻底改变了对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 锂的抗触发和情绪稳定作用的生化基础 仍然有待充分阐明。 阐明机制 锂可以稳定边缘的潜在失调和 边缘相关功能还提供了描述的潜力 BD的基础病因/病理生理学。 固有的主要问题 然而，神经药物研究是归因的困难 与任何观察到的生化发现的治疗相关性。 一个潜力 将治疗意义归因于任何生化发现的方法是 确定由属于属于的药物修饰的常见生化靶标 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））。 大量数据显示了 锂对PKC信号通路产生了重大影响。 大多数 但是，数据是从临床前啮齿动物研究得出的，因此 排除对这些治疗相关性的充分理解 生化发现。 这些研究表明两个重要且高度 临床上相关的未来研究方向：首先，这很重要 确定PKC信号通路的类似调制是否也是 由其他药理学剂带来的，在 BD的处理，例如VPA；其次，最终至关重要 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 预测因素。 因此，在此提案中，调查员的具体 目的是：1）表征VPA对PKC信号的影响 大脑中的途径。 为了归因于潜在的治疗相关性 对于生化发现，将与 锂：a）在特定的大脑区域，b）在临床上有意义的 时间剖面，即急性，长期以来，在药物治疗之后 戒断和药物重新服用。 2）确定关系 在锂或VPA诱导的PKC信号系统中的变化之间 大鼠脑和大鼠外周细胞；最终，调查员希望 确定治疗引起的PKC变化之间的关系 BD患者的信号传导系统和治疗反应。 演示 中枢神经系统的变化与外围的关系之间的关系 啮齿动物将允许对BD患者进行随后的研究。 这是 势在必行，因为为了建立任何任何 生化发现，有必要证明：a） 实际上，生化效应确实发生在管理的患者中 临床相关范式中的药理学剂； b）那里 是生化变化与治疗反应之间的关系。 最终，阐明锂和VPA稳定的机制 情绪应该改善发展更有效的前景 长期治疗，以及鉴定生化预测因子 治疗反应。