Inhibitor Reprogramming of a Human Histone Deacetylase Protein Interaction Network

人类组蛋白脱乙酰酶蛋白相互作用网络的抑制剂重编程

• 批准号: 9198990
• 负责人: MICHAEL P WASHBURN
• 金额: $ 31.76万
• 依托单位: STOWERS INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9198990
• 关键词: Acetylation; Active Sites; Affect; Affinity Chromatography; Apoptosis; Binding; Biochemical; Biological; Biological Assay; Breast Cancer cell line; Cancer cell line; Cell Communication; Cell Line; Cells; Chromatin Remodeling Factor; Clinical Trials; Complex; Cutaneous; Development; Disease; Enzymes; FDA approved; Future; Gene Expression; Genomic approach; Genomics; Goals; HDAC1 gene; HDAC2 gene; Histone Deacetylase; Histone Deacetylase Inhibitor; Histones; Human; Investments; MS-275; Malignant Neoplasms; Mediating; Modeling; Pathway Analysis; Patients; Pharmaceutical Preparations; Play; Proteins; Proteomics; Publications; Publishing; Recurrent disease; Refractory; Role; Specificity; T-Cell Lymphoma; Technology; Testing; Therapeutic; Thinking; United States; Vorinostat; base; cell growth; cell type; human disease; inhibitor/antagonist; innovation; insight; novel; protein complex; public health relevance; response; therapeutic target; treatment strategy; triple-negative invasive breast carcinoma

 DESCRIPTION (provided by applicant): Histone deacetylases (HDACs) play important roles in cancer, and the FDA approved HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA), is used for the treatment of advanced and refractory cutaneous T-cell lymphoma in patients with progressive, persistent, or recurrent disease. SAHA is part of more than 225 clinical trials. Inhibition of HDAC activity results in altered acetylation of core histones and other proteins that cause changes in gene expression, resulting in cell growth arrest and apoptosis. However, despite the massive investment the United States has made into the study of SAHA as a drug for human disease treatment, it is routinely stated that the mechanism of action of SAHA remains poorly understood. Recent findings from our lab suggest that SAHA and HDAC inhibitors actually have broader, noncatalytic effects on HDAC complexes. Here we will use innovative biochemical, quantitative proteomic, computational, and genomic technologies to further elucidate the mechanism of action of SAHA. In particular, we will analyze the SAHA induced disruption of a human HDAC protein interaction network and determine which fraction of SAHA induced gene expression changes can be accounted for by disrupting this network. In specific aim 1 we will complete our assembly of the protein interaction network and biochemically dissect the multiple complexes present in this network. Furthermore, we will develop novel computational approaches for protein interaction network assembly and determine the strength of interactions in this network. In specific aim two, we will finalize our analysis of the SAHA induced dynamics of the network and dissect the gene expression changes resulting from network disruption. In the third specific aim, we will carry out focused studies on a breast cancer cell line and compare these results to the standard cell line used in specific aims 1 and 2. By comparing and contrasting these results, we will determine the cell specific effects of SAHA on this human HDAC network. Upon completion of this application, we will have a detailed understanding in multiple cell types of the effects of SAHA on a histone protein interaction network and the resulting gene expression changes mediated by the disruption of this network. This information will yield novel insights into the mechanism of action of SAHA and facilitate future development of novel HDAC inhibitors.

 描述（由申请人提供）： 组蛋白去乙酰化酶（HDAC）在癌症中起重要作用，并且FDA批准的HDAC抑制剂辛二酰苯胺异羟肟酸（SAHA）用于治疗患有进行性、持续性或复发性疾病的患者中的晚期和难治性皮肤T细胞淋巴瘤。SAHA是超过225项临床试验的一部分。HDAC活性的抑制导致核心组蛋白和其他蛋白质的乙酰化改变，从而引起基因表达的变化，导致细胞生长停滞和凋亡。然而，尽管美国对SAHA作为人类疾病治疗药物的研究进行了大量投资，但通常认为SAHA的作用机制仍然知之甚少。我们实验室最近的研究结果表明，SAHA和HDAC抑制剂实际上对HDAC复合物具有更广泛的非催化作用。在这里，我们将使用创新的生物化学，定量蛋白质组学，计算和基因组技术，以进一步阐明SAHA的作用机制。特别是，我们将分析SAHA诱导的人类HDAC蛋白相互作用网络的破坏，并确定SAHA诱导的基因表达变化的哪一部分可以通过破坏该网络来解释。在具体目标1中，我们将完成蛋白质相互作用网络的组装，并以生物化学的方式剖析该网络中存在的多个复合物。此外，我们将开发新的蛋白质相互作用网络组装的计算方法，并确定在这个网络中的相互作用的强度。在具体目标二中，我们将完成我们对SAHA诱导的网络动力学的分析，并剖析网络中断导致的基因表达变化。在第三个具体目标中，我们将对乳腺癌细胞系进行重点研究，并将这些结果与具体目标1和2中使用的标准细胞系进行比较。通过比较和对比这些结果，我们将确定SAHA对该人类HDAC网络的细胞特异性影响。在完成本申请后，我们将详细了解在多种细胞类型的 SAHA对组蛋白相互作用网络的影响以及由此引起的由该网络的破坏介导的基因表达变化。这些信息将产生新的见解， SAHA的作用机制，并促进未来新的HDAC抑制剂的开发。