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

HDAC 抑制剂对 HDAC3 及其伙伴之间相互作用的影响

• 批准号: 8365841
• 负责人: JOEL M. GOTTESFELD
• 金额: $ 1.28万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8365841
• 关键词: Acetylation; Ataxia; Biology; Cell Culture Techniques; Complex; Disease; Friedreich Ataxia; Funding; Fungal Genome; Gene Silencing; Genes; Genetic Transcription; Grant; HDAC3 gene; Histone Deacetylase Inhibitor; Histones; Introns; Lead; Molecular; Mutation; National Center for Research Resources; Neurodegenerative Disorders; Principal Investigator; Proteins; Proteomics; Research; Research Infrastructure; Resources; Source; Therapeutic; Triplet Multiple Birth; United States National Institutes of Health; base; cost; effective therapy; frataxin; improved; in vivo; mouse model; nervous system disorder; protein complex; transcription factor

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.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 弗里德里希（Friedreich）的共济失调是一种由FXN基因的第一个内含子中GAA-TTC三胞胎的不稳定高度扩张引起的进行性神经退行性疾病，它编码了必需的蛋白质frataxin。该突变会干扰基因转录，并​​基于以下假设：FXN基因上核心组蛋白的乙酰化状态可能是其沉默的原因，我们已经开发了一种新的组蛋白脱乙酰基酶（HDAC）抑制剂，这些抑制剂会反向逆Frataxin基因在细胞中逆转的基因抑制剂培养和疾病的小鼠模型。通过使用活性分析探针的蛋白质组学研究，我们将HDAC3鉴定为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，并且与各种转录因子相互作用。为了帮助阐明FXN沉默和重新激活的分子机制，我们希望在存在和不存在HDAC抑制剂的情况下确定HDAC3相互作用的伴侣。目前，弗里德里希（Friedreich）的共济失调尚无有效的治疗方法，对HDAC抑制剂对HDAC3复合物的影响可能会导致这种毁灭性神经系统疾病的新和改善的治疗剂。