Molecular control of HDAC4-mediated neuroprotection

HDAC4 介导的神经保护的分子控制

• 批准号: 7524223
• 负责人: Santosh R D'Mello
• 金额: $ 18.73万
• 依托单位: UNIVERSITY OF TEXAS DALLAS
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7524223
• 关键词: Apoptosis; Biological Factors; Biological Process; Cell Cycle; Cell Cycle Inhibition; Cell Death; Cessation of life; Condition; Development; Enzymes; Family; Foundations; Genes; Goals; HDAC4 gene; Histone Deacetylase; Histones; Human; Investigation; Lead; Mass Spectrum Analysis; Mediating; Molecular; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Pathology; Patients; Protein Family; Proteins; Public Health; Quality of life; Signal Pathway; Signal Transduction Pathway; Societies; Therapeutic; Work; base; cost; insight; member; nervous system disorder; neuron apoptosis; neuron loss; neuronal survival; neuroprotection; novel; novel strategies; prevent

DESCRIPTION (provided by applicant): A common feature of neurodegenerative diseases is the aberrant and excessive loss of neurons by activation of apoptosis. Numerous molecules involved in the promotion or inhibition of neuronal apoptosis have been identified and these are being organized as components of signal transduction pathways. This proposal focuses on histone deacetylases (HDACs), a family of enzymes originally identified on the basis of their ability to deacetylate histones. More recent work has shown that HDACs are involved in a variety of different biological processes and they have therefore emerged as the subject of intense investigation. We have found that one member of the HDAC family of proteins, HDAC4, protects neurons from apoptosis. Neuroprotection does not involve signaling pathways that are commonly used by other survival-promoting genes and biological factors. The objective of the proposal is to use a multi-pronged approach to elucidate the mechanism by which HDAC4 exerts its neuroprotective action with the long-term goal of developing novel and effective strategies to prevent cell death in neurodegenerative pathologies. The specific aims are- (1) To identify the region within HDAC4 that mediates neuroprotection, (2) To identify HDAC4-interacting proteins in neurons using mass-spectrometry, and (3) To identify downstream targets of HDAC4 action in neurons with a focus on cell cycle components. PUBLIC HEALTH RELEVANCE: Neurological diseases disrupt the quality of life for patients and cost society billions of dollars annually. While symptomatic treatments are available for many neurological diseases, a cure is not presently available. Identifying molecules that regulate neuronal survival and understanding the mechanism by which they act would lead to the development of more effective therapeutic strategies. Our proposal focuses on HDAC4, a protein that is neuroprotective. It is our hope that the results from the studies we propose will shed insight into how HDAC4 exerts its neuroprotective effect and thus provide novel strategies to prevent neuronal loss in neurodegenerative conditions.

描述（由申请人提供）：神经退行性疾病的一个共同特征是通过细胞凋亡的激活导致神经元的异常和过度损失。许多参与促进或抑制神经元凋亡的分子已被鉴定，并且这些分子被组织为信号转导途径的组分。该建议集中于组蛋白脱乙酰酶（HDAC），这是一个最初基于其脱乙酰化组蛋白的能力而鉴定的酶家族。最近的研究表明，HDAC参与了各种不同的生物过程，因此它们已成为深入研究的主题。我们已经发现，HDAC蛋白家族的一个成员HDAC 4保护神经元免于凋亡。神经保护不涉及通常由其他存活促进基因和生物因子使用的信号通路。该提案的目的是使用多管齐下的方法来阐明HDAC 4发挥其神经保护作用的机制，其长期目标是开发新的有效策略来预防神经退行性病变中的细胞死亡。具体目标是-（1）鉴定HDAC 4内介导神经保护的区域，（2）使用质谱法鉴定神经元中的HDAC 4相互作用蛋白，以及（3）鉴定神经元中HDAC 4作用的下游靶点，重点是细胞周期组分。 公共卫生相关性：神经系统疾病破坏了患者的生活质量，每年给社会造成数十亿美元的损失。虽然对症治疗可用于许多神经系统疾病，但目前还没有治愈方法。识别调节神经元存活的分子并理解它们的作用机制将导致更有效的治疗策略的发展。我们的建议集中在HDAC 4，一种具有神经保护作用的蛋白质。我们希望我们提出的研究结果将深入了解HDAC 4如何发挥其神经保护作用，从而提供预防神经退行性疾病中神经元丢失的新策略。