Molecular control of HDAC4-mediated neuroprotection

描述（由申请人提供）：神经退行性疾病的一个共同特征是细胞凋亡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经被确定，这些分子被组织为信号转导途径的组成部分。这一建议的重点是组蛋白去乙酰化酶（hdac），这是一个酶家族，最初是根据它们对组蛋白去乙酰化的能力而确定的。最近的研究表明，hdac参与多种不同的生物过程，因此它们已成为深入研究的主题。我们发现HDAC蛋白家族的一个成员，HDAC4，可以保护神经元免于凋亡。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。该提案的目的是使用多管齐下的方法来阐明HDAC4发挥其神经保护作用的机制，并开发新的有效策略来预防神经退行性病变中的细胞死亡。具体目的是：(1)确定HDAC4中介导神经保护的区域，(2)使用质谱法鉴定神经元中HDAC4相互作用的蛋白，以及(3)确定HDAC4在神经元中作用的下游靶点，重点关注细胞周期成分。

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.