Molecular control of HDAC4-mediated neuroprotection

描述(申请人提供)：神经退行性疾病的一个共同特征是由于细胞凋亡的激活而导致神经元的异常和过度丢失。许多参与促进或抑制神经元凋亡的分子已经被识别出来，这些分子正在被组织起来，作为信号转导通路的组成部分。这项提议的重点是组蛋白脱乙酰酶(HDAC)，这是一个酶家族，最初是根据它们对组蛋白进行脱乙酰化的能力而确定的。最近的工作表明，HDAC参与了各种不同的生物过程，因此它们已成为密集研究的对象。我们发现，HDAC家族中的一种蛋白质HDAC4可以保护神经元免受凋亡的影响。神经保护不涉及其他促进生存的基因和生物因素通常使用的信号通路。该提案的目的是用多管齐下的方法阐明HDAC4发挥神经保护作用的机制，长期目标是开发新的有效策略来防止神经退行性病变中的细胞死亡。其具体目的是：(1)确定HDAC4内介导神经保护的区域，(2)使用质谱学确定神经元中与HDAC4相互作用的蛋白，以及(3)确定神经元中HDAC4作用的下游靶点，重点是细胞周期成分。 公共卫生相关性：神经系统疾病扰乱了患者的生活质量，每年给社会造成数十亿美元的损失。虽然许多神经系统疾病都有对症治疗，但目前还没有治愈方法。识别调节神经元存活的分子并了解它们的作用机制将导致开发更有效的治疗策略。我们的建议重点是HDAC4，一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有助于深入了解HDAC4如何发挥其神经保护作用，从而为防止神经退行性疾病中的神经元丢失提供新的策略。

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.