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

 描述(申请人提供)：双相情感障碍是一种慢性疾病，通常使人虚弱。锂和丙戊酸盐仍然是在这种疾病中使用最广泛的情绪稳定剂。然而，它们并不是对每个人都有效，它们会产生显著的副作用。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，锂治疗会导致某些组蛋白脱乙酰酶的下调。使用显示许多人类疾病特征的鼠标，我们发现锂和丙戊酸盐都会导致其异常表型的逆转。此外，如果我们用更具选择性的HDAC抑制剂来治疗这些小鼠，我们发现这些药物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)胆囊素(CCK)基因启动子的组蛋白乙酰化增加，这些组蛋白乙酰化的变化在治疗反应中是重要的。这些数据使我们假设，选择性HDAC抑制剂可能在治疗双相情感障碍方面具有治疗作用，由于它们的选择性，它们的副作用将比丙戊酸盐少得多，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，在这项建议中，我们将在我们的小鼠身上测试化合物，这些化合物只对一到两个特定的I类HDAC蛋白具有高度选择性。如果这些化合物成功地逆转了突变小鼠的躁狂表型，那么它们或其他类似的化合物可能会进入治疗双相情感障碍的临床试验。除了直接的翻译研究外，我们还想了解这些HDAC抑制剂的作用机制。我们将重点放在VTA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，而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下调VTA的多巴胺神经元中单独的I类HDAC蛋白的表达，以确定我们是否能够准确地识别需要抑制哪些HDAC才能产生治疗效果。我们还将观察组蛋白乙酰化的变化，这些变化发生在VTA中，特别是CCK启动子中，对药物抑制的反应。最后，由于CCK不是丙戊酸治疗后唯一改变的基因，我们计划使用下一代测序技术的组合来确定在HDAC抑制剂治疗后VTA的多巴胺神经元中增强的重要靶基因。这将把我们引向未来治疗发展的其他潜在目标。

 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.