SIRT1 and the control of neuronal survival

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。这项建议的重点是sirtuins，一个家庭的脱乙酰化酶，是激烈的调查，因为他们在各种不同的生物过程中的作用，包括调节神经变性的主题。像其他一些实验室一样，我们发现sirtuin蛋白之一SIRT1可以保护神经元免于凋亡。但与以前的研究结论相反，我们发现SIRT1的神经保护作用是由一种新的非催化机制介导的。该提案的目的是使用多管齐下的方法来阐明SIRT 1发挥其神经保护作用的新机制。具体目标是：（1）鉴定SIRT1内介导神经保护的区域，（2）鉴定神经元中SIRT1作用的下游靶点和机制，以及（3）使用质谱法鉴定神经元中SIRT1相互作用蛋白。这项研究的长期目标是开发新的和有效的策略，以防止神经退行性病变中的细胞死亡。 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SIRT1上，这是一种保护神经元免受变性的蛋白质。我们希望我们提出的研究结果将深入了解SIRT1如何发挥其神经保护作用，从而提供新的策略来预防神经退行性疾病中的神经元丢失。

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 sirtuins, a family of deacetylating enzymes that are the subject of intense investigation because of their role in a variety of different biological processes including the regulation of neurodegeneration. Like some other labs, we have found that one of the sirtuin proteins, SIRT1, protects neurons from apoptosis. But contrary to the conclusions of previous studies, we find that neuroprotection by SIRT1 is mediated by a novel, non-catalytic mechanism. The objective of the proposal is to use a multi- pronged approach to elucidate the novel mechanism by which SIRT1 exerts its neuroprotective action. The specific aims are - (1) to identify the region within SIRT1 that mediates neuroprotection, (2) to identify downstream targets and mechanism of SIRT1 action in neurons, and (3) to identify SIRT1-interacting proteins in neurons using mass-spectrometry. The long term goal of this research is to develop novel and effective strategies to prevent cell death in neurodegenerative pathologies. 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 SIRT1, a protein that protects neurons from degeneration. It is our hope that the results from the studies we propose will shed insight into how SIRT1 exerts its neuroprotective effect and thus provide novel strategies to prevent neuronal loss in neurodegenerative conditions.