EFFECT OF HDAC INHIBITORS ON THE INTERACTION BETWEEN HDAC3 AND ITS PARTNERS

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 弗里德赖希共济失调是一种进行性神经退行性疾病，由编码必需蛋白共济失调蛋白的FXN基因的第一内含子中GAA-TTC三联体的不稳定过度扩增引起。这种突变干扰基因转录，并且基于FXN基因上核心组蛋白的乙酰化状态可能导致其沉默的假设，我们开发了一类新的组蛋白脱乙酰酶（HDAC）抑制剂，其在细胞培养物和该疾病的小鼠模型中逆转共济失调蛋白基因沉默。通过使用活性分析探针的蛋白质组学研究，我们已经将HDAC 3确定为我们的HDAC抑制剂的靶标，但是我们的分子增加FXN基因表达的机制尚不清楚。HDAC3是体内不同蛋白质复合物的一部分，并与各种转录因子相互作用。为了帮助阐明FXN沉默和再激活的分子机制，我们希望在HDAC抑制剂存在和不存在的情况下鉴定HDAC 3相互作用伴侣。目前还没有有效的治疗弗里德赖希？的共济失调和HDAC抑制剂对HDAC3复合物的影响的研究可以导致这种毁灭性的神经系统疾病的新的和改进的治疗方法。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Friedreich's ataxia is a progressive neurodegenerative disorder caused by the unstable hyper-expansion of GAA-TTC triplets in the first intron of the FXN gene, that encodes the essential protein frataxin. This mutation interferes with gene transcription and, based on the hypothesis that the acetylation status of core histones on the FXN gene might be responsible for its silencing, we have developed a new class of histone deacetylase (HDAC) inhibitors that reverse frataxin gene silencing in cell culture and in a mouse model of the disease. Through proteomic studies using an activity profiling probe we have identified HDAC3 as the target of our HDAC inhibitors, but the mechanism by which our molecules increase the expression of the FXN gene is unknown. HDAC3 is part of different protein complexes in vivo and interacts with various transcription factors. To help elucidate the molecular mechanism underlying the silencing and reactivation of FXN, we wish to identify HDAC3 interacting partners in the presence and absence of HDAC inhibitors. Currently there is no effective treatment for Friedreich?s ataxia and the study of the effect of HDAC inhibitors on HDAC3 complexes can lead to new and improved therapeutics for this devastating neurological disorder.