PKC SIGNALING AND THE TREATMENT OF BIPOLAR DISORDER

描述(摘自申请者的摘要)：BD，躁郁症 疾病是一种严重的、慢性的、终生的致残性疾病。 患病率为1.2%。锂作为一种生物燃料的功效的发现 情绪稳定剂使BD患者的治疗发生了革命性的变化， 但是，尽管它是精神病学最重要的治疗方法之一， 锂的抗躁狂和稳定情绪作用的生化基础 仍有待充分阐明。阐明其作用机制(S) 锂稳定了一种潜在的边缘和神经功能失调 边缘相关函数还提供了描绘 BD的潜在病因/病理生理学。一个固有的主要问题是 然而，神经药理学研究很难归因于 与任何观察到的生化发现相关的治疗。一种潜力 将治疗相关性归因于任何生化结果的方法是 确定由以下药物修饰的常见生化指标 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 锂在PKC信号通路中起着重要作用。大多数 然而，数据来自于临床前的啮齿动物研究，因此 排除了对这些治疗相关性的充分理解 生化结果。这些研究表明有两个重要的和高度的 未来研究的临床相关方向：第一，它很重要 为了确定PKC信号通路是否也有类似的调制 由其他已被证明有效的药理药物在 VPA等BD的治疗；第二，最终 阐明这些生化变化与临床的关系 反应，这可能导致生化和/或遗传的鉴定 结果的预言者。因此，在这项建议中，调查员的具体 目的是：1)研究VPA对PKC信号转导的影响 大脑中的一条通路。为了归因于潜在的治疗相关性 关于生化结果，他们将被同时调查 锂：a)在特定的大脑区域，以及b)在临床上有意义的 时间分布，即急性的、慢性的、用药后的 停药和重新用药。2)确定关系 锂和丙戊酸诱导的PKC信号系统改变之间的关系 大鼠脑和大鼠外周细胞中；最终，研究人员希望 确定治疗引起的蛋白激酶C变化之间的关系 BD患者的信号系统和治疗反应。演示 中枢神经系统和外周的变化之间的关系 啮齿动物将允许对BD患者进行后续调查。这是 势在必行，因为为了建立治疗相关性， 生化结果，有必要证明：a)这些 事实上，生物化学效应确实发生在服用 临床相关范例中的药理药物；以及b)有 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 情绪应该是改善发展的更有效的前景 长期治疗，并用于确定生化预测因素 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.