RNA-binding Factors Implicated in Neurogenesis, Alzheimer's Disease, and other Neurodegenerative Pathologies

与神经发生、阿尔茨海默病和其他神经退行性疾病相关的 RNA 结合因子

• 批准号: 10688820
• 负责人: Myriam Gorospe
• 金额: $ 40.21万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10688820
• 关键词: Abeta synthesis; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease patient; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Antisense Oligonucleotides; Area; Brain; Cells; Cellular biology; Collaborations; Collection; Developmental Biology; Drug Delivery Systems; Elderly; FMR1; FMRP; Gene Expression; Glioblastoma; Goals; Heterogeneous-Nuclear Ribonucleoprotein Group C; Heterogeneous-Nuclear Ribonucleoproteins; Human; Malignant Neoplasms; Medicine; Mitochondria; Mitochondrial RNA; Molecular Biology; Mus; Nature; Nerve Degeneration; Neurons; Parkinson Disease; Pathology; Peptides; Physiology; Plasma; Post-Transcriptional Regulation; Process; Production; Protein Biosynthesis; Proteolysis; RNA; RNA Binding; Regulation; Reporting; Role; Senile Plaques; Sirtuins; Testing; Time; Toxic effect; Work; age related; beta-site APP cleaving enzyme 1; circular RNA; extracellular vesicles; frontier; neurogenesis; programs; senescence; structural biology; transcriptomics

Several studies are underway in the RNA Regulation Section to investigate the gene expression programs that influence neuronal physiology and pathology, with particular emphasis on neurodegeneration. During this review period, we have studied the transcriptomic programs of senescent cells that modulate amyloid plaques in Alzheimers disease (AD). In this project area, we previously reported that the levels of amyloid precursor protein (APP), which is cleaved to release the Alzheimers disease hallmark peptide Abeta, was regulated by RBPs FMRP (fragile X mental retardation protein) and hnRNP C (heterogeneous nuclear ribonucleoprotein C) (Lee et al., Nature Structural and Molecular Biology, 2010), as well as by the RBP HuD (Kang et al., Cell Reports 2014). This earlier led us to propose that HuD jointly promotes the production of APP and the cleavage of its amyloidogenic fragment, Abeta. Work is underway to investigate the potential use of antisense oligonucleotides (ASOs) to lower HuD levels, which we hypothesize would in turn lower the levels of APP and BACE1 in human and mouse. After reporting the presence of mitochondrial RNA in Alzheimer's disease circulating extracellular vesicles (Kim et al., Frontiers in Cell and Developmental Biology, 2020), we have identified collections of circular RNAs differentially abundant in brains and plasma from AD patients (Cochran et al., Cells 2021). We also supported a number of collaborative studies that uncovered that loss of mitochondrial sirtuins (SIRT3) caises hyperexcitability of the neuronal network accelerates age-related A pathology, and sensitizes neurons to A toxicity (NeuroMolecular Medicine, 2021). In collaboration with the King lab, we reviewed the impact of an RBP that we have studied for a long time, HuR, on glioblastoma, a malignancy that increases with advancing age (Advanced Drug Delivery Reviews, 2022).

RNA调节部分正在进行一些研究，以研究影响神经元生理学和病理学的基因表达程序，并特别强调神经退行性。在此审查期间，我们研究了在阿尔茨海默氏病（AD）中调节淀粉样蛋白斑块的衰老细胞的转录组计划。 在该项目领域，我们先前报道说，淀粉样的前体蛋白（APP）的水平被裂解以释放阿尔茨海默氏病标志性肽ABETA，受RBPS FMRP（脆弱的X智力低下蛋白质）和HNRNP C（异构核核核酸蛋白c）（learopor c）（letary and artary et al andy anty and Al anty and sornation et an s natural et an and hernp c）调节。 RBP HUD（Kang等人，细胞报告2014）。这之前促使我们提出HUD共同促进APP的产生及其淀粉样蛋白生成片段Abeta的裂解。正在研究反义寡核苷酸（ASO）对HUD水平降低的潜在用途，我们假设这将降低人和小鼠中APP和BACE1的水平。 在报道了在阿尔茨海默氏病中存在线粒体RNA之后，我们循环细胞外囊泡（Kim等人，细胞和发育生物学的前沿，2020年），我们已经确定了圆形RNA在大脑中差异丰富的圆形RNA的集合，来自AD患者的大脑和血浆（Cochran等人，Cochran等人，Cell al。，Cell。，Cell。，20221）。 我们还支持了许多合作研究，这些研究发现了线粒体Sirtuins（SIRT3）的丧失，这使神经元网络的过度兴奋性加速了与年龄相关的病理学，并使神经元对毒性（神经分子医学，2021年）敏感。 在与国王实验室的合作中，我们回顾了很长一段时间以来研究的RBP的影响，HUR，对胶质母细胞瘤，这种恶性肿瘤随着年龄的增长而增加（高级药物提供评论，2022年）。