PKC SIGNALING AND THE TREATMENT OF BIPOLAR DISORDER

描述（改编自申请人摘要）：BD，躁狂抑郁症 疾病是一种严重、慢性和致残性疾病， 发病率为1.2%。 锂作为一种 情绪稳定剂彻底改变了对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， 锂抗躁狂和稳定情绪作用的生化基础 还有待于充分阐明。 阐明其机制， 锂稳定了边缘系统的潜在失调， 边缘相关功能也提供了描绘 BD的潜在病因学/病理生理学。 一个固有的主要问题是， 然而，神经药理学研究的困难在于， 与任何观察到的生化发现的治疗相关性。 一个潜在 将治疗相关性归因于任何生化发现的方法是， 确定由属于以下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 (e.g.,锂和丙戊酸（VPA））。 大量数据显示， 锂对PKC信号通路有重要影响。 大部分 然而，数据来自临床前啮齿动物研究，因此 排除了对这些治疗相关性的充分理解， 生化发现 这些研究表明，两个重要的和高度 未来研究的临床相关方向：首先，重要的是 以确定PKC信号通路的类似调节是否也 由其他药理学药物引起，已证实在 治疗BD，如VPA;第二，最终 阐明这些生化变化与临床 反应，这可能导致识别生物化学和/或遗传 预测结果。 因此，在本提案中，研究人员的具体 目的：1）研究VPA对PKC信号通路的影响 大脑中的通路。 为了将潜在的治疗相关性 生物化学的发现，他们将同时进行调查， 锂：a）在特定的大脑区域，和B）在临床上有意义的 时间特征，即急性、慢性、用药后 停药和重新给药。 2)确定关系 锂或VPA诱导的PKC信号系统的变化之间， 大鼠脑和大鼠外周细胞;最终研究者希望 确定治疗诱导的PKC变化与 信号系统和BD患者的治疗反应。 示范 中枢神经系统和外周神经系统的变化之间的关系， 啮齿类动物将允许在BD患者中进行后续研究。 这是 这是必要的，因为为了建立任何治疗相关性， 生物化学研究结果，有必要证明：a）这些 事实上，生化效应确实发生在服用 在临床相关范例中的药理学试剂;和B）存在 是生化变化和治疗反应之间的关系。 最终，阐明了锂和VPA稳定 情绪应该改善的发展前景更有效 长期治疗，并用于确定生化预测因子 治疗反应。

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.