Mechanisms of Neuroprotection by Histone Deacetylase Inhibition

组蛋白脱乙酰酶抑制的神经保护机制

基本信息

批准号：
7461900
负责人：
RICHARD S MORRISON
金额：
$ 34.13万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-03-01 至 2013-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7461900
关键词：
Acetylation Acute Apoptosis Regulator Apoptotic Attention BH3 Domain Brain Injuries Cell Death Cell Death Signaling Process Cells Cessation of life Chronic Clinical Complex DNA Damage Data Development Disease Drosophila genus Effectiveness Event Genetic Transcription Histone Deacetylase Histone Deacetylase Inhibitor Histone deacetylase inhibition Human Huntington Disease Injury Laboratories Lead Mediating Mitochondria Molecular Nervous System Trauma Neurodegenerative Disorders Neuroglia Neurologic Neuronal Dysfunction Neurons Nuclear Phenotype Post-Translational Protein Processing Proliferating Protein p53 Proteins Proteomics Public Health Range Severities Signal Transduction Stress TP53 gene Testing Therapeutic Agents Transgenic Mice Work base cancer cell human Huntingtin protein inhibitor/antagonist mitochondrial dysfunction molecular site mouse model mutant nervous system disorder neuron apoptosis neuron loss neuroprotection novel novel therapeutics prevent protective effect protein expression

项目摘要

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.

描述（由申请人提供）：肿瘤抑制因子p53被认为是急性和慢性神经损伤和神经退行性疾病中细胞凋亡的重要调节剂。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 p53 依赖性的组蛋白脱乙酰酶 (HDAC) 复合物蛋白表达增加。该数据表明 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防止 p53 介导的细胞死亡。相比之下，癌细胞中的 HDAC 活性通常升高，并且 HDAC 抑制实际上会诱导 p53 依赖性细胞死亡。在本申请中，基于HDAC抑制剂作用的神经元特异性模式的这一新发现，我们建议通过检查HDAC抑制剂如何阻断神经元细胞来检验神经元中p53介导的细胞死亡信号传导依赖于组蛋白脱乙酰酶活性的假设死亡。我们将具体：1) 确定 HDAC 抑制剂是否选择性保护神经元免受 p53 介导的细胞死亡，2) 确定 HDAC 抑制剂是否直接阻断神经元中 p53 依赖性细胞死亡所需的 p53 激活和/或转录活性； 3) 确定 HDAC 抑制剂是否可以阻止 p53 依赖性线粒体完整性变化。该提案的目的将帮助我们更好地了解 HDAC 抑制剂作用的分子位点和机制，从而增强这些抑制剂作为神经系统疾病和损伤治疗药物的效用。公共健康相关性：组蛋白脱乙酰酶抑制剂可保护几种人类神经退行性疾病小鼠模型中的神经元免于死亡。然而，组蛋白脱乙酰酶抑制剂防止细胞死亡的机制尚不清楚。更好地了解这些化合物如何发挥作用以及它们可预防的疾病或伤害类型将扩大它们的作用范围和有效性。我们建议确定组蛋白脱乙酰酶抑制剂如何阻止神经元细胞死亡，这可能导致开发用于治疗神经系统疾病和神经系统损伤的新治疗药物。