The Role of HDAC6 and Glucocorticoid Signaling in Resilience to Depression

描述（由申请人提供）：本项目是我们实验室长期致力于阐明抑郁症恢复力和抗抑郁药（ATD）疗效的分子机制的一部分。更好地了解这些机制对于发现新的更有效的抗抑郁疗法至关重要。组蛋白去乙酰化酶（HDAC）抑制剂，一种在大脑中促进蛋白质超乙酰化的药物，在应激相关疾病的啮齿动物模型中显示出一致的行为活动。到目前为止，大多数研究都是在染色质重塑机制的背景下解释HDAC抑制剂（HDACi）的抗抑郁样特征。然而，现在已经确定赖氨酸乙酰化的影响远远超出了转录调节。事实上，最近的蛋白质组学检查表明，组蛋白仅代表乙酰酶的一小部分。为了确定哪些机制构成了hdac抗抑郁活性的真正介质，现在至关重要的是检查hdac的非组蛋白底物在小鼠抑郁和应激恢复模型中的参与。HDAC6是HDAC家族成员，在神经元中仅定位于细胞质。这一特性使其成为介导HDACi对非组蛋白作用的一线候选者。其他研究小组在非神经元系统中进行的研究表明，HDAC6是糖皮质激素受体（GR）伴侣复合物的重要调节剂，这是糖皮质激素信号传导所必需的。我们的实验室发现，HDAC6在血清素能神经元中特别丰富，我们已经报道过，在这些细胞中缺乏HDAC6的小鼠表现出更强的行为弹性。在此，我们提出验证HDAC6调控GR信号介导HDAC6 KO对弹性影响的假设。我们将通过使用激光捕获显微解剖和微阵列技术检查HDAC6缺失对gr介导的基因转录的影响来做到这一点。我们还将研究在血清素神经元缺乏HDAC6的小鼠中，皮质酮诱导的行为改变的差异。这些结果可能为抑郁症和其他压力相关疾病的治疗提供一个重要的新靶点，这些疾病目前构成了重大的经济和社会负担。

DESCRIPTION (provided by applicant): This project is part of our laboratory's long-term efforts to elucidate the molecular mechanisms responsible for resilience to depression and antidepressant (ATD) efficacy. A greater understanding of these mechanisms is critical to the discovery of novel and more effective antidepressant therapies. Histone deacetylase (HDAC) inhibitors, drugs that promote protein hyperacetylation in the brain, have demonstrated consistent behavioral activity in rodent models of stress-related disorders. Thus far, most studies have interpreted the antidepressant-like profile of HDAC inhibitors (HDACi) in the context of chromatin-remodeling mechanisms. However, it is now well established that the influence of lysine acetylation extends far beyond transcriptional regulation. In fact recent proteomic examinations indicate that histones represent only a fraction of the the acetylome. To determine which mechanisms constitute bona fide mediators of the antidepressant activity of HDACi, it is now crucial to examine the participation of non- histone substrates of HDACs in murine models of depression and stress resiliency. HDAC6 is an HDAC family member which, in neurons, localizes exclusively to the cytoplasm. This feature makes it a first line candidate to mediate effects of HDACi on non-histone proteins. Studies conducted by other groups in non-neuronal systems have shown that HDAC6 is an important modulator of the glucocorticoid receptor (GR) chaperone complex required for proper corticosteroid signaling. Our laboratory has found that HDAC6 is particularly enriched in serotonergic neurons, and we have reported that mice lacking HDAC6 in these cells show increased behavioral resilience. Here we propose to test the hypothesis that HDAC6 regulation of GR signaling mediates the effect of the HDAC6 KO on resilience. We will do this by examining the effects of loss of HDAC6 on GR-mediated gene transcription using laser capture microdissection and microarray technology. We will also examine differences in corticosterone-induced behavioral changes in mice lacking HDAC6 specifically in serotonin neurons. These results could provide an important new target for the treatment of depression and other stress-related disorders, which currently present a significant economic and societal burden. PUBLIC HEALTH RELEVANCE: This proposal seeks to examine the value of HDAC6 as a novel target for antidepressant and pro-resilience interventions. For a subset of patients suffering from depression and posttraumatic stress disorder, there are currently no effective treatments. If our hypothesis that loss of HDAC6 enhances resilience to stress via inhibition of glucocorticoid signaling proves correct, it could open a promising new avenue of therapeutic interventions for these disorders.