Mechanisms of Neuroprotection by Histone Deacetylase Inhibition

描述(由申请人提供)：肿瘤抑制基因P53被认为是急、慢性神经损伤和神经退行性疾病中细胞凋亡的重要调节因子。然而，神经元中P53激活的下游分子后果仍然不清楚。我们的蛋白质组学分析表明，DNA损伤诱导的神经元凋亡涉及组成组蛋白脱乙酰酶(HDAC)复合体的蛋白表达依赖于P53的增加。这一数据表明，P53可能通过激活组蛋白脱乙酰酶活性来促进神经元功能障碍/细胞死亡。我们的初步研究确实表明，组蛋白脱乙酰酶抑制剂可以保护P53介导的细胞死亡。相比之下，癌细胞中的HDAC活性普遍升高，而抑制HDAC实际上会诱导依赖于P53的细胞死亡。在目前的应用中，基于对HDAC抑制剂作用的神经元特异性模式的这一新发现，我们建议通过研究HDAC抑制剂如何阻止神经细胞死亡来检验这一假设，即神经元中P53介导的细胞死亡信号依赖于组蛋白脱乙酰酶的活性。我们将具体：1)确定HDAC抑制剂是否选择性地保护神经元免受P53介导的细胞死亡的影响；2)确定HDAC抑制剂是否直接阻止神经元中P53依赖的细胞死亡所需的P53激活和/或转录活性；以及3)确定HDAC抑制剂是否阻止P53依赖的线粒体完整性的变化。这一建议的目的将有助于我们更好地了解HDAC抑制剂的分子部位和作用机制，从而提高这些抑制剂作为神经疾病和损伤的治疗药物的效用。 公共卫生相关性：组蛋白脱乙酰酶抑制剂在几种人类神经退行性疾病的小鼠模型中保护神经元免于死亡。然而，组蛋白脱乙酰酶抑制剂阻止细胞死亡的机制尚不清楚。更好地了解这些化合物是如何发挥作用的，以及它们所预防的疾病或伤害的类型，将提高它们的作用范围和有效性。我们建议确定组蛋白去乙酰酶抑制剂如何阻止神经细胞死亡，这可能导致开发新的治疗药物来治疗神经系统疾病和神经系统损伤。

DESCRIPTION (provided by applicant): The tumor suppressor p53 is recognized as an important regulator of apoptosis in acute and chronic neurological insults and neurodegenerative disorders. However, the downstream molecular consequences of p53 activation in neurons still remain obscure. Our proteomic analyses have demonstrated that DNA damage-induced neuronal apoptosis involves a p53-dependent increase in the expression of proteins that comprise histone deacetylase (HDAC) complexes. This data suggests that p53 might promote neuronal dysfunction/cell death by activating histone deacetylase activity. Our preliminary studies indeed demonstrate that histone deacetylase inhibitors protect against p53-mediated cell death. In contrast HDAC activity is generally elevated in cancer cells, and HDAC inhibition actually induces p53-dependent cell death. In the present application, based on this novel finding of the neuron-specific mode of HDAC inhibitor actions, we propose to test the hypothesis that p53-mediated cell death signaling in neurons is dependent on histone deacetylase activity by examining how HDAC inhibitors block neuronal cell death. We will specifically: 1) Determine if HDAC inhibitors selectively protect neurons from p53-mediated cell death, 2) Determine if HDAC inhibitors directly block p53 activation and/or transcriptional activity required for p53-dependent cell death in neurons; and 3) Determine if HDAC inhibitors prevent p53- dependent changes in mitochondrial integrity. The aims of this proposal will help us to better understand the molecular sites and mechanism of HDAC inhibitor action, which will enhance the utility of these inhibitors as therapeutic agents for neurological diseases and injury. PUBLIC HEALTH RELEVANCE: Histone deacetylase inhibitors protect neurons from dying in several mouse models of human neurodegenerative disease. However, the mechanism by which histone deacetylase inhibitors prevent cell death is not understood. A better understanding of how these compounds work and the types of diseases or injuries that they protect against would enhance their range of action and their effectiveness. We propose to determine how histone deacetylase inhibitors block neuronal cell death which could lead to the development of new therapeutic agents for treating neurological diseases and nervous system injury.