Consequences of HDAC2 Inhibition in VTA-NAc circuitry

从家长补助金 摘要 双相情感障碍是一种常见的精神疾病，治疗选择很少，无法治愈。一个最 治疗急性躁狂和稳定情绪的常用处方药是抗惊厥药 药物，丙戊酸盐（VPA;商品名Depakote）。自20世纪90年代中期以来一直使用这种药物，但没有 每个人对VPA的疗效反应都是一样的，它可以产生多种，通常是严重的副作用， 方面的影响.此外，VPA具有多种分子靶点，目前尚不清楚哪些靶点具有治疗作用 相关的更好地理解VPA使躁狂正常化的分子机制， 这将在未来导致更有针对性的治疗，从而产生更高的治疗反应和更少的副作用。 在这项资助的第一个资助周期中，我们发现VPA的治疗作用似乎是通过它的 抑制称为组蛋白脱乙酰基酶2（HDAC 2）的蛋白质，特别是在大脑的一部分， 腹侧被盖区（VTA）有大量多巴胺能神经元。HDAC 2参与调节 因此，虽然这种蛋白质的抑制可能比VPA更有针对性， 治疗后，仍然有利于我们识别出那些表达改变的重要基因 HDAC 2抑制在腹侧被盖区。为了确定这些目标，我们将首先确定哪些基因通常被结合 通过HDAC 2和什么样的变化，组蛋白乙酰化发生在响应HDAC 2抑制VTA使用两个 动物模型具有与人类躁狂症惊人相似的行为特征， 在VTA的活动。然后，我们将确定哪些基因和蛋白质表达的变化发生与HDAC 2 抑制和联合收割机结合这些结果与第一个目标，我们以前的结果，以确定特定的 可能成为治疗候选物的蛋白质。在目标3中，我们将确定HDAC 2的影响 HDAC 2对VTA多巴胺能活性和信号传导的抑制和定向靶基因， 有助于确定HDAC 2靶基因可能使人类躁狂症正常化的机制。总的来说，这 这项研究将帮助我们确定新的治疗靶点及其治疗双相情感障碍的作用机制。 disorder.

From parent grant ABSTRACT Bipolar disorder is a common psychiatric disease with few treatment options and no cure. One of the most commonly prescribed medications for treatment of acute mania and mood stabilization is the anticonvulsant drug, valproate (VPA; trade name Depakote). This medication has been used since the mid-1990s, however not everyone responds equally to VPA in terms of therapeutic efficacy and it can produce multiple, often severe side effects. Moreover, VPA has a variety of molecular targets and it is unclear which targets are therapeutically relevant. Better understanding of the molecular mechanisms that normalize mania in response to VPA could lead to more targeted treatments in the future which produce a higher therapeutic response with less side effects. In the first funding cycle of this grant, we discovered that the therapeutic actions of VPA appear to occur via it’s inhibition of a protein called histone deacetylase 2 (HDAC2) specifically in a part of the brain that contains a large number of dopaminergic neurons, the ventral tegmental area (VTA). HDAC2 is involved in the regulation of gene expression on a wide scale, so while the inhibition of this protein is perhaps more targeted than VPA treatment, it is still advantageous for us to identify the important genes who’s expression is changed as a result of HDAC2 inhibition in the VTA. To identify these targets, we will first determine which genes are normally bound by HDAC2 and what changes to histone acetylation occur in response to HDAC2 inhibition in the VTA using two animal models that have a behavioral profile that is strikingly similar to human mania and increased dopaminergic activity in the VTA. We will then determine which gene and protein expression changes occur with HDAC2 inhibition and combine these results with those of the first Aim, and our prior results, to determine the particular proteins that might be likely therapeutic candidates. In Aim 3 we will then determine the impact of HDAC2 inhibition and direct target genes of HDAC2 on VTA dopaminergic activity and signaling in our mouse models to help identify the mechanisms by which HDAC2 target genes might normalize human mania. Taken together, this study will help us to identify novel therapeutic targets and their mechanism of action for the treatment of bipolar disorder.