In vivo and in vitro roles played by Hdac3 in genomic stability maintenance

Hdac3 在基因组稳定性维持中发挥的体内和体外作用

基本信息

批准号：
7614663
负责人：
Srividya Bhaskara
金额：
$ 5.53万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-29 至 2011-09-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7614663
关键词：
Acetylation Acute Myelocytic Leukemia Affect Age Age-Months Alleles Antineoplastic Agents Apoptosis B-Cell Development B-Lymphocytes Biochemical Biological Assay Biological Models Cell Cycle Cell Cycle Checkpoint Cell Cycle Progression Cell Death Cell Line Cells Chimeric Proteins Chromatin Chromatin Structure Chromosomal Breaks Chromosomal translocation Clinical Trials Complex DNA Damage DNA Repair Data Deposition Development Disease Double Strand Break Repair Embryo Engineering Enzymes Epigenetic Process Fibroblasts Gene Deletion Gene Expression Genes Genetic Transcription Genome Stability Genomic Instability Germ Lines Hematopoiesis Hepatomegaly Histone Acetylation Histone Deacetylase Histone Deacetylase Inhibitor Histone H3 Histone H4 Histones Hormones Immunoglobulin Class Switching Immunoglobulin Switch Recombination In Vitro Ionizing radiation Knockout Mice Lipids Liver Lysine Maintenance Malignant Neoplasms Metabolism Microarray Analysis Mus Mutation Nonhomologous DNA End Joining Nuclear Oncogenes Pathway interactions Phase Phase II Clinical Trials Phosphorylation Physiological Play Primary carcinoma of the liver cells Process Recruitment Activity Research Role SECTM1 gene Signal Transduction Pathway Societies Testing Therapeutic Transferase Trichostatin A Tumor Suppressor Genes Vorinostat Work base cell killing cohort design gene function in vivo inhibitor/antagonist insight mouse model neoplastic cell repaired response t(8 21)(q22 q22)

项目摘要

DESCRIPTION (provided by applicant): This proposal is designed to understand the role played by epigenetic marks in normal and disease condition states. Chromosomal translocations that occur in various cancers can create fusion proteins, and these fusion proteins recruit histone deacetylases (HDACs) to repress the transcription of tumor suppressors and genes that are important for cellular differentiation. Pharmacological inhibitors of HDACs are in Phase I and Phase II clinical trials for various cancers, yet we still do not have a clear understanding of how broad-spectrum HDAC inhibitors (HDIs) kill cells or trigger differentiation. So far, studies to understand the action of histone deacetylase inhibitors have been limited to cell lines that lack critical cell cycle checkpoints. Therefore, to understand the physiological functions of HdacS, a HDAC enzyme that plays a very important role in nuclear hormone and other cell cycle signal transduction pathways, we created a conditional HdacS knockout mouse model. The preliminary data obtained after conditional deletion of HdacS in primary mouse embryo fibroblast cells gave us a vast amount of information on the vital roles of HdacS in cell cycle progression, DNA damage control and DNA repair. We found that HdacS causes DNA damage that in turn leads to apoptosis. This DNA damage is observed only in cycling cells and not in noncycling cells. Also, loss of HdacS causes genome instability in MEFs and hepatocellular carcinoma in mice. This proposal will further provide insight to the mechanistic functions for HdacS in genome stability maintenance using the mouse model system. The specific aims are: 1) Elucidate the mechanism by which loss of HdacS affects DNA repair and cell cycle progression in vitro. 2) Examination of the in vivo requirements for HdacS in B-cell development. This work will not only provide a mechanistic basis for the action of histone deacetylase inhibitors but also has very important therapeutic benefits in treatment of various cancers. The proposed work to understand functions of HdacS will facilitate the design of better and more specific inhibitors to HDAC enzymes. This research will help us to provide the society with a better cure for cancer by designing more specific cancer drugs for clinical trials.

描述（由申请人提供）：该提案旨在了解表观遗传标记在正常和疾病状态下所发挥的作用。各种癌症中发生的染色体易位可以产生融合蛋白，这些融合蛋白招募组蛋白脱乙酰酶 (HDAC) 来抑制肿瘤抑制因子和对细胞分化很重要的基因的转录。 HDAC 的药理学抑制剂正处于针对各种癌症的 I 期和 II 期临床试验中，但我们仍然对广谱 HDAC 抑制剂 (HDI) 如何杀死细胞或触发分化没有清楚的了解。到目前为止，了解组蛋白脱乙酰酶抑制剂作用的研究仅限于缺乏关键细胞周期检查点的细胞系。因此，为了了解HdacS（一种在核激素和其他细胞周期信号转导途径中起着非常重要作用的HDAC酶）的生理功能，我们创建了条件性HdacS基因敲除小鼠模型。在原代小鼠胚胎成纤维细胞中条件性删除 HdacS 后获得的初步数据为我们提供了大量有关 HdacS 在细胞周期进展、DNA 损伤控制和 DNA 修复中重要作用的信息。我们发现 HdacS 会导致 DNA 损伤，进而导致细胞凋亡。这种 DNA 损伤仅在循环细胞中观察到，而不是在非循环细胞中观察到。此外，HdacS 的缺失会导致 MEF 和小鼠肝细胞癌的基因组不稳定。该提案将进一步深入了解 HdacS 在使用小鼠模型系统维持基因组稳定性方面的机制功能。具体目标是：1) 阐明 HdacS 缺失影响体外 DNA 修复和细胞周期进展的机制。 2) 检查 B 细胞发育中 HdacS 的体内需求。这项工作不仅将为组蛋白脱乙酰酶抑制剂的作用提供机制基础，而且在治疗各种癌症方面具有非常重要的治疗益处。拟议的了解 HdacS 功能的工作将有助于设计更好、更特异的 HDAC 酶抑制剂。这项研究将帮助我们通过设计更具体的癌症药物进行临床试验，为社会提供更好的癌症治疗方法。