Lymphoma development in the elderly: Perturbed posttranscriptional regulation

老年人淋巴瘤的发展：转录后调节受到干扰

• 批准号: 9891939
• 负责人: Ronald B Gartenhaus
• 金额: --
• 依托单位: BALTIMORE VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9891939
• 关键词: ATM gene; Age; Aging; Antigens; Ataxia Telangiectasia; Attenuated; B-Lymphocytes; Cellular Stress Response; DNA Damage; Defect; Development; Elderly; Event; Exhibits; Exposure to; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Genotoxic Stress; Goals; Human; Incidence; Individual; Link; Lymphocyte; Lymphoma; Lymphomagenesis; Malignant Neoplasms; Mediating; Messenger RNA; MicroRNAs; Modeling; Molecular; Mus; Non-Hodgkin' s Lymphoma; Oncogenic; Operon; Patients; Peripheral Blood Lymphocyte; Phosphotransferases; Post-Transcriptional Regulation; Proteins; RNA; RNA-Binding Proteins; Regulation; Regulator Genes; Research; Role; Signal Pathway; Signal Transduction; Toxic effect; Transcript; Veterans; Work; aging population; ataxia telangiectasia mutated protein; attenuation; clinically relevant; functional decline; genome integrity; improved; insight; large cell Diffuse non-Hodgkin' s lymphoma; mortality; mouse model; protein expression; public health relevance; response; sensor

 DESCRIPTION (provided by applicant): Project Summary/Abstract The goals of this project are to understand the mechanistic basis for the increased incidence of diffuse large B cell lymphoma (DLBCL) associated with aging in humans. It has been known for decades that aging mice frequently develop lymphomas and work in mouse models have identified age-associated reduction in the DNA damage response (DDR). The ATM gene, a master regulator of the DNA damage-signaling pathways is responsible for ataxia-telangiectasia (AT), and is essential for maintaining the integrity of the genome. The Levine group demonstrated that the function of ATM kinase declines significantly with age in mice. Of clinical relevance, human peripheral blood lymphocytes from older individuals also demonstrate an attenuated response after exposure to genotoxic stresses. Interestingly, a significant percentage of DLBCL exhibited elevated levels of the oncogenic microRNA-421 which down-regulates levels of ATM protein. The levels of expressed genes are controlled through both transcriptional and post-transcriptional/translational events after genotoxic stress exposure. RNA-binding proteins (RBP) and microRNAs are major posttranscriptional/ translational regulators of gene expression. This synchronized regulation of mRNA subsets is the basis of the post-transcriptional "RNA-operon" model whereby RBPs coregulate multiple mRNAs and thereby regulate the co-expression of proteins with related function. The RBP, HuR is recognized as a key post-transcriptional regulator of mRNAs encoding proteins central to the cellular stress response. Our group recently identified those transcripts differentially associated with HuR, including multiple cancer-related mRNAs in an ATM/Chk2- dependent manner. The specific hypothesis to be investigated is that the aberrant posttranscriptional regulation of genes by HuR in response to IR contributes to lymphomagenesis in the elderly. In Specific Aim 1, we will investigate the linkage between aberrant post-transcriptional regulation of genes and aging in human B- cell lymphocytes. In Specific Aim 2, we will investigate if the oncogenic microRNA-421 contributes to DLBCL development. In Specific Aim 3, we will investigate whether the development of splenic lymphomas in aging mouse are mechanistically linked with defects in post-transcriptional gene regulation. Our proposal should provide a functional link between ATM and HuR's posttranscriptional role in mediating oncogenic, and antiapoptotic activities as well as to validat the paradigm that the age-associated decline in function of ATM underlies the increased incidence of non-Hodgkin's lymphoma (NHL) observed with increasing age.

 描述（由申请人提供）： 项目概要/摘要本项目的目的是了解与人类衰老相关的弥漫性大B细胞淋巴瘤（DLBCL）发病率增加的机制基础。几十年来，人们已经知道衰老的小鼠经常发生淋巴瘤，并且在小鼠模型中的工作已经确定了与年龄相关的DNA损伤反应（DDR）的减少。ATM基因是DNA损伤信号通路的主要调节因子，是共济失调-毛细血管扩张症（AT）的致病基因，对维持基因组的完整性至关重要。Levine小组证明，ATM激酶的功能随着小鼠年龄的增长而显著下降。具有临床意义的是，老年人外周血淋巴细胞在暴露于遗传毒性应激后也表现出减弱的反应。有趣的是，显著百分比的DLBCL表现出致癌microRNA-421水平升高，其下调ATM蛋白水平。基因毒性应激暴露后，通过转录和转录后/翻译事件控制表达基因的水平。RNA结合蛋白（RBP）和microRNA是基因表达的主要转录后/翻译调节因子。mRNA亚群的这种同步调节是转录后“RNA操纵子”模型的基础，其中RBP共调节多个mRNA，从而调节具有相关功能的蛋白质的共表达。RBP，HuR被认为是编码细胞应激反应中心蛋白质的mRNA的关键转录后调节因子。我们的小组最近确定了那些与HuR差异相关的转录本，包括ATM/Chk 2依赖性方式的多种癌症相关mRNA。有待研究的具体假设是，异常的转录后调控的基因HuR在响应IR有助于淋巴瘤的老年人。在特定目标1中，我们将研究人类B细胞淋巴细胞中基因转录后调控异常与衰老之间的联系。在特定目标2中，我们将研究致癌microRNA-421是否有助于DLBCL的发展。在具体目标3中，我们将研究老年小鼠脾淋巴瘤的发展是否与转录后基因调控缺陷有机械联系。我们的建议应该提供一个ATM和HuR的转录后作用之间的功能联系，在介导致癌和抗凋亡活动，以及验证的范例，即年龄相关的ATM功能下降的基础上，随着年龄的增长观察到的非霍奇金淋巴瘤（NHL）的发病率增加。