Selective HDAC inhibition and therapeutic target genes: Identification of novel treatments for Bipolar Disorder

 描述（由申请人提供）：双相情感障碍是一种慢性且经常使人衰弱的疾病。锂和丙戊酸盐仍然是这种疾病中最广泛使用的情绪稳定剂。然而，它们并不是对每个人都有效，并且会引起严重的副作用。已知丙戊酸盐是组蛋白脱乙酰酶（HDAC）蛋白的抑制剂，最近的研究还发现锂治疗会导致某些HDAC的下调。使用显示出人类疾病的许多特征的小鼠，我们发现锂和丙戊酸盐都导致其异常表型的逆转。此外，如果我们用更具选择性的HDAC抑制剂治疗这些小鼠，我们发现这些抑制剂也能够使它们的躁狂样表型正常化。此外，在以前的研究中，我们确定锂治疗导致腹侧被盖区（VTA）胆固醇激肽（Cck）基因启动子处组蛋白乙酰化的增加，并且组蛋白乙酰化的这些变化在治疗反应中很重要。这些数据使我们假设选择性HDAC抑制剂可能在双相情感障碍的治疗中具有治疗性，并且由于其选择性，它们的副作用远小于丙戊酸盐，丙戊酸盐抑制许多不同的HDAC并改变其他蛋白质的功能。因此，在本提案中，我们将在我们的小鼠上测试仅对一种或两种特定的I类HDAC蛋白具有高度选择性的化合物。如果这些化合物能够成功逆转突变小鼠的躁狂样表型，那么它们或其他类似的化合物就可以进入治疗双相情感障碍的临床试验。除了直接翻译研究，我们还想了解这些HDAC抑制剂的作用机制。我们专注于腹侧被盖区作为这些化合物的潜在作用部位，因为该区域富含多巴胺能神经元，并且多巴胺被认为与躁狂发作的沉淀密切相关。此外，我们正在使用病毒介导的基因转移来敲低腹侧被盖区多巴胺神经元中单个I类HDAC蛋白的表达，以确定我们是否可以准确地识别哪些HDAC（或HDAC）需要被抑制以产生治疗效果。我们还将研究组蛋白乙酰化的变化，这些变化发生在对药物抑制的反应中，无论是在VTA中还是在Cck启动子中。最后，由于Cck不是丙戊酸盐治疗改变的唯一基因，我们计划使用下一代测序技术的组合来确定HDAC抑制剂治疗后腹侧被盖区多巴胺神经元中增强的重要靶基因。这将使我们找到未来治疗开发的其他潜在目标。

 DESCRIPTION (provided by applicant): Bipolar disorder is a chronic and often debilitating disease. Lithium and Valproate remain the most widely used mood stabilizing agents in this disorder. However, they are not effective for everyone and they cause significant side effects. Valproate is known to be an inhibitor of histone deacetylase (HDAC) proteins and recent studies also find that lithium treatment leads to a downregulation of certain HDACs. Using a mouse that displays many features characteristic of human disorder, we have found that both lithium and valproate lead to a reversal of their abnormal phenotypes. Furthermore, if we treat these mice with much more selective HDAC inhibitors, we find that these are also capable of normalizing their manic-like phenotypes. Moreover, in previous studies we determined that lithium treatment leads to an increase in histone acetylation at the promoter of the Cholecystokinin (Cck) gene in the ventral tegmental area (VTA) and that these changes in histone acetylation are important in the therapeutic response. These data led us to hypothesize that selective HDAC inhibitors might be therapeutic in the treatment of bipolar disorder and because of their selectivity, they will hav far fewer side effects than valproate which inhibits many different HDACs and alters the function of other proteins. Thus in this proposal we will test compounds on our mice which are highly selective for only one or two specific class I HDAC proteins. If these compounds are successful at reversing the manic-like phenotype of the mutant mice, then they, or others like them, could move forward into clinical trials for the treatment of bipolar disorder. In addition to the direct translational studies, we want to understand the mechanisms by which these HDAC inhibitors are working. We are focusing on the VTA as a potential site of action for these compounds since this area is enriched in dopaminergic neurons and dopamine is thought to be keenly involved in the precipitation of manic episodes. Moreover, we are using viral mediated gene transfer to knock-down the expression of individual class I HDAC proteins in the dopamine neurons of the VTA to determine if we can identify exactly which HDAC (or HDACs) need to be inhibited to produce a therapeutic effect. We will also look at the changes in histone acetylation that occur in response to pharmacological inhibition both globally in the VTA and specifically at the Cck promoter. Finally, since Cck is not the only gene that is altered by valproate treatment, we plan to use a combination of next generation sequencing techniques to determine the important target genes that are enhanced in the dopamine neurons of the VTA following treatment with HDAC inhibitors. This will lead us to other potential targets for future treatment development.