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）： 项目摘要/摘要该项目的目标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患上淋巴瘤，并在小鼠中发挥作用。模型已确定 DNA 损伤反应 (DDR) 与年龄相关的减少，ATM 基因是 DNA 损伤信号通路的主要调节因子，负责共济失调毛细血管扩张 (AT)，并且对于维持神经系统的完整性至关重要。 Levine 小组证明，在小鼠中，ATM 激酶的功能随着年龄的增长而显着下降，具有临床意义的是，在暴露于致癌性 microRNA-421 水平后，人外周血淋巴细胞的反应也减弱。 - 调节 ATM 蛋白的水平。基因毒性 RNA 结合蛋白暴露后，通过转录和转录后/翻译事件来控制表达基因的水平。 (RBP) 和 microRNA 是基因表达的主要转录后/翻译调节因子，这种 mRNA 子集的同步调节是转录后“RNA-操纵子”模型的基础，通过该模型，RBP 共同调节多个 mRNA，从而调节蛋白质的共表达。 RBP、HuR 被认为是编码细胞应激反应核心蛋白的关键转录后调节因子，我们的研究小组最近发现了与 HuR 存在差异相关的转录本，其中包括多种。以 ATM/Chk2 依赖性方式与癌症相关的 mRNA。要研究的具体假设是 HuR 响应 IR 的异常转录后调节导致老年人的淋巴瘤发生。在特定目标 2 中，我们将研究致癌性 microRNA-421 是否有助于 DLBCL 的发展。具体目标 3，我们将研究衰老小鼠脾淋巴瘤的发生是否与转录后基因调控缺陷存在机制联系。我们的建议应提供 ATM 和 HuR 在介导致癌和抗凋亡活性中的转录后作用之间的功能联系。验证以下范式：与年龄相关的 ATM 功能下降是随年龄增加观察到的非霍奇金淋巴瘤 (NHL) 发病率增加的基础。