Lithium's Mode of Action: Genetic Etiology and Drug Disovery in Bipolar Disorder

描述（由申请人提供）：双相情感障碍（BD）是一种高度遗传性神经行为障碍，影响全球约1%的人口，是当今世界死亡和残疾的最重要原因之一。锂在1949年首次用于治疗躁狂症，并且在过去的30年里一直是双相情感障碍的主要治疗方法，证明对多达约50%的治疗病例有效。然而，尽管锂的疗效已得到证实，但至少有一半的病例对治疗没有积极反应，毒性是一个关键问题，需要对患者的几个生物学参数进行常规监测。现有的少数替代治疗（如丙戊酸盐）在临床环境或比较试验中未显示出成功率的改善。尽管经过数十年的协同研究，锂的功效模式仍然未知。基因组学和化学的最新技术和概念发展目前使强大的药物发现方法，有可能从根本上改善目标识别，化合物发现和药物开发的过程。在本研究中，我们提出了应用化学基因组学来阐明锂的治疗作用模式和发现治疗BD的新化合物。这项工作将利用新兴的方法，需要定义的表达签名，高通量筛选的化学库在基于细胞的测定，以概括这些签名，其次是表征小分子的线索，使用形态学和其他细胞测定。我们假设，在细胞内的目标分子通路的定义将确定介导锂的功效和分离具有高合理的药物开发潜力的化合物的主要细胞过程。值得注意的是，锂的作用模式的任何解决方案都可能表明常见疾病状态的分子病因学基础的遗传途径。虽然我们打算描绘锂靶向的分子途径和由此产生的细胞效应，但该提案的驱动重点是快速鉴定具有开发治疗药物和高度特异性试剂的潜力的新型化合物，用于实验解剖与精神疾病相关的途径。

DESCRIPTION (provided by applicant): Bipolar disorder (BD) is a highly heritable neurobehavioral disorder that affects ~1 % of the global population and constitutes one of the most significant causes of death and disability in the world today. Lithium was first used to treat mania in 1949 and has remained the mainstay treatment of Bipolar disorder for the last 30 years, proving effective for as many as -50% of treated cases. However, despite lithium's demonstrated efficacy, at least half of cases do not respond positively to treatment, and toxicity is a critical concern requiring routine monitoring of several biological parameters in patients. The few alternative treatments that exist, such as Valproate, do not present improved success rates in clinical settings or comparative trials. Despite decades of concerted research, lithium's mode of efficacy remains unknown. Recent technological and conceptual developments in genomics and chemistry currently enable powerful approaches to drug discovery that have the potential to radically improve the processes of target identification, compound discovery, and drug development. In the present study, we propose the application of chemical genomics to the elucidation of lithium's therapeutic mode of action and the discovery of novel compounds for the treatment of BD. The effort will take advantage of emerging methodologies entailing the definition of expression signatures, high-throughput screening of chemical libraries in cell-based assays to recapitulate those signatures, followed by characterization of small molecule leads using morphological and other cellular assays. We hypothesize that in cellulo definition of targeted molecular pathways will identify the primary cellular processes that mediate lithium's efficacy and isolate compounds with high rational potential for drug development. Notably, any resolution of lithium's mode of action will likely indicate genetic pathways underlying the molecular etiology of the common disease state. While we intend to delineate the molecular pathways targeted by lithium and the resultant cellular effects, a driving focus of this proposal is the rapid identification of novel compounds with the potential for development of therapeutic drugs and highly specific reagents for experimental dissection of pathways relevant to psychiatric disorders.