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: 9280607
• 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 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9280607
• 关键词: ATM gene; ATM wt Allele; 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; Genotoxic Stress; Goals; Human; Incidence; Individual; Lead; Link; Lymphocyte; Lymphoma; Lymphomagenesis; Malignant Neoplasms; Mediating; Messenger RNA; MicroRNAs; Modeling; Molecular; Mus; Non-Hodgkin' s Lymphoma; Oncogenic; Operon; Patients; Peripheral Blood Lymphocyte; Phosphotransferases; Population; Post-Transcriptional Regulation; Proteins; RNA; RNA-Binding Proteins; Regulation; Regulator Genes; Research; Role; Signal Pathway; Signal Transduction; Toxic effect; Transcript; Veterans; Work; abstracting; aged; ataxia telangiectasia mutated protein; attenuation; base; 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）： 项目摘要/摘要该项目的目标是了解与人类衰老相关的扩散大B细胞淋巴瘤（DLBCL）的发病率增加的机理基础。数十年来，老化小鼠经常发展淋巴瘤，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损伤信号途径的主要调节剂，负责共济失调 - 凝血症（AT），对于维持基因组的完整性至关重要。 Levine组表明，随着小鼠的年龄，ATM激酶的功能显着下降。临床相关性，老年人的人外周血淋巴细胞也表现出暴露于遗传毒性应激后的衰减反应。有趣的是，DLBCL很大一部分暴露于致癌的MicroRNA-421的升高水平，该水平下调了ATM蛋白水平。遗传毒性应激暴露后，通过转录和转录后/翻译事件来控制表达基因的水平。 RNA结合蛋白（RBP）和microRNA是基因表达的主要后/翻译调节剂。 mRNA子集的这种同步调节是转录后“ RNA-Operon”模型的基础，RBPS核心核心核心多个mRNA，从而调节蛋白质与相关功能的共表达。 RBP HUR被认为是编码针对细胞应激反应中心的蛋白质的mRNA的关键转录调节剂。我们的小组最近确定了与HUR相关的成绩单，包括以ATM/CHK2依赖性方式的多个与癌症相关的mRNA。要研究的具体假设是，HUR对IR响应IR的基因转录后的异常调节有助于古老的淋巴瘤发生。在特定目标1中，我们将研究人B细胞淋巴细胞中基因的转录后调节和衰老之间的联系。在特定的目标2中，我们将调查致癌的MicroRNA-421是否有助于DLBCL的发展。在特定的目标3中，我们将研究衰老小鼠中脾淋巴瘤的发展是否与转录后基因调控中的缺陷有关。我们的提议应在ATM和HUR在介导致癌性和抗凋亡活动中的转录后作用之间提供功能联系，并确认ATM与年龄相关的功能下降的范式增加了与年龄较高的非霍奇金淋巴瘤（NHL）的发生率的增加。