Alzheimer's Administrative Supplement - An antisense RNA-mediated regulatory program that drives cancer metastasis

阿尔茨海默氏症行政补充——一种驱动癌症转移的反义 RNA 介导的调控程序

• 批准号: 10117474
• 负责人: Hani Goodarzi
• 金额: $ 40.38万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10117474
• 关键词: 3' Untranslated Regions; Administrative Supplement; Affect; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Antisense RNA; Apoptosis; Autophagocytosis; Binding; Bioinformatics; Biological Assay; Biology; Brain; Brain region; Breast Cancer Cell; Breast Cancer Patient; Breast Epithelial Cells; Cell Death; Cell physiology; Cells; Cellular Stress; Clinical; Computer Models; Data; Data Set; Disease; Dissection; Enhancers; Enzymes; Future; Genetic Transcription; Genetic study; Goals; Growth; High-Throughput Nucleotide Sequencing; Homeostasis; Iron; Lipid Peroxidation; Malignant Neoplasms; Measures; Mediating; Messenger RNA; Metabolic; Metastatic to; Methods; Molecular; NQO1 gene; Names; Neoplasm Metastasis; Neurons; Normal Cell; Oligonucleotides; Outcome; Oxidation-Reduction; Oxidative Stress; Pathologic; Pathology; Pathway interactions; Play; Poly A; Polyadenylation; Preparation; Process; Protein Isoforms; Proteins; RNA; RNA Binding; RNA-Binding Proteins; Reactive Oxygen Species; Regulatory Pathway; Relapse; Research; Resistance; Role; Sampling; Site; Technology; Transfer RNA; Untranslated RNA; Up-Regulation; Xenograft Model; Xenograft procedure; base; biological systems; cancer cell; clinically relevant; differential expression; experimental study; human disease; in vivo; induced pluripotent stem cell; insight; mRNA Expression; mRNA Stability; malignant breast neoplasm; molecular phenotype; mouse model; nervous system disorder; neuron loss; novel; novel therapeutics; overexpression; oxidative damage; programs; promoter; recruit; response; therapeutic target; transcription factor; transcriptome sequencing; tumor; tumor progression

PROJECT SUMMARY Ferroptosis is a recently discovered pathway of programmed cell death, which involves iron and reactive oxygen species (ROS). Ferroptosis is distinct from apoptosis, autophagy and other forms of cell death. While it was first discovered in cancer, it has now been implicated in several neurologic diseases, including Alzheimer's disease (AD). Hallmarks of ferroptosis, e.g. lipid peroxidation and iron dysregulation, have long been observed in brain samples from AD patients. Genetic studies in mouse models of AD also support a substantial role for ferroptosis in neuronal death. Therefore, there is a clear need for better elucidating the regulatory pathways of ferroptosis that play a role in AD. We recently discovered a new regulatory program that modulates ferroptotic cell death in cancer cells. This pathway is especially intriguing as it involves an antisense RNA as the underlying mater regulator. We have names this antisense RNA NQO1-AS as it is transcribed from a promoter on the positive strand coinciding with the 3'UTR of gene NQO1. NQO1 is a redox protein and we have shown that the NQO1-AS modulates the redox state of the cell through binding and stabilization of the NQO1 mRNA. More importantly, this NQO1-AS/NQO1 regulatory axis plays a role in ferroptosis. We have shown that silencing NQO1-AS or NQO1 sensitizes cells to ferroptotic cell death following oxidative stress. Having discovered this new pathway, we asked whether evidence of its activity could be found in other biological systems. Interesting, we observed a significant reduction in NQO1 mRNA expression and stability in Alzheimer's disease datasets from the regions of the brain most affected by this pathology. This reduction persisted even in microdissected samples, which control for general neuronal loss. Given these findings, we see a strong case for the involvement of the NQO1-NQO1-AS in AD, and therefore we have taken steps to extend our studies in cancer cells to iPSC- derived neurons in models of Alzheimer's disease. The successful completion of this study will dissect the possible role of NQO1-mediated ferroptosis in AD and may provide new therapeutic pathways that restore NQO1 activity through synthetic oligos that mimic NQO1-AS and restore higher NQO1 activity.

项目摘要 铁凋亡是最近发现的编程细胞死亡的途径，涉及铁和反应性 氧（ROS）。铁凋亡与细胞凋亡，自噬和其他形式的细胞死亡不同。同时 它最初是在癌症中发现的，现在与几种神经系统疾病有关，包括阿尔茨海默氏症 疾病（AD）。铁凋亡的标志，例如长期观察到脂质过氧化和铁失调 在AD患者的大脑样本中。 AD小鼠模型中的遗传研究也支持 神经元死亡中的铁凋亡。因此，显然需要更好地阐明 在AD中发挥作用的铁氧作用。我们最近发现了一个新的监管计划，该计划调节了铁毒性 癌细胞中的细胞死亡。该途径特别有趣，因为它涉及反义RNA作为基础 母校调节器。我们有这个反义rna nqo1-，因为它是从启动子上转录的 正链与基因NQO1的3'UTR一致。 NQO1是一种氧化还原蛋白，我们已经表明 NQO1-AS通过NQO1 mRNA的结合和稳定来调节细胞的氧化还原状态。更多的 重要的是，该NQO1-AS/NQO1调节轴在铁铁作用中起作用。我们已经表明了沉默 NQO1-AS或NQO1使细胞在氧化应激后将细胞敏感到铁凋亡细胞死亡。发现了这个 新的途径，我们询问是否可以在其他生物系统中找到其活性的证据。有趣的， 我们观察到阿尔茨海默氏病数据集的NQO1 mRNA表达和稳定性显着降低 来自受此病理影响最大的大脑区域。这种降低甚至在微分解中也持续 样品，控制一般神经元丧失。鉴于这些发现，我们看到了参与的有力案例 AD中的NQO1-NQO1-AS，因此我们已经采取了措施将癌细胞的研究扩展到IPSC- 在阿尔茨海默氏病模型中衍生的神经元。这项研究的成功完成将剖析 NQO1介导的亚铁蛋白的可能作用在AD中，并可能提供新的治疗途径来恢复NQO1 通过合成的寡寡做的活性，可以模仿NQO1-AS并恢复较高的NQO1活性。