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

基本信息

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
项目类别：
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&apos Untranslated Regions Administrative Supplement Affect Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos 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

项目摘要

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.

项目概要铁死亡是最近发现的一种程序性细胞死亡途径，涉及铁和反应性细胞死亡。氧物质（ROS）。铁死亡不同于细胞凋亡、自噬和其他形式的细胞死亡。虽然它最初是在癌症中发现的，现在它与多种神经系统疾病有关，包括阿尔茨海默病疾病（AD）。铁死亡的标志，例如脂质过氧化和铁失调，早已被观察到 AD 患者的大脑样本中。 AD 小鼠模型的遗传研究也支持了 AD 的重要作用神经元死亡中的铁死亡。因此，显然需要更好地阐明监管途径铁死亡在 AD 中发挥作用。我们最近发现了一种新的调节程序，可以调节铁死亡癌细胞中的细胞死亡。该途径特别有趣，因为它涉及反义 RNA 作为基础母调节器。我们将这种反义 RNA 命名为 NQO1-AS，因为它是从正链与基因 NQO1 的 3'UTR 重合。 NQO1 是一种氧化还原蛋白，我们已经证明 NQO1-AS 通过结合和稳定 NQO1 mRNA 来调节细胞的氧化还原状态。更多的重要的是，NQO1-AS/NQO1 调节轴在铁死亡中发挥作用。我们已经证明沉默 NQO1-AS 或 NQO1 使细胞对氧化应激后的铁死亡细胞敏感。发现这一点后新途径，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病数据集中 NQO1 mRNA 表达和稳定性显着降低来自受这种病理影响最严重的大脑区域。即使在显微解剖中，这种减少仍然持续存在样本，控制一般神经元损失。鉴于这些发现，我们看到了参与的充分理由 AD 中 NQO1-NQO1-AS 的研究，因此我们已采取措施将癌细胞研究扩展到 iPSC- 阿尔茨海默病模型中衍生的神经元。本研究的成功完成将剖析 NQO1 介导的铁死亡在 AD 中的可能作用，并可能提供恢复 NQO1 的新治疗途径通过模拟 NQO1-AS 的合成寡核苷酸活性并恢复更高的 NQO1 活性。