Role of long non-coding RNAs in exosome biogenesis

长非编码RNA在外泌体生物发生中的作用

• 批准号: 10713910
• 负责人: Fatemeh Momen Heravi
• 金额: $ 41.13万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-10 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10713910
• 关键词: Biogenesis; Biological Process; Biology; Cell Communication; Cell membrane; Cell physiology; Cells; Cellular Stress; Code; Cytoplasm; Data; Development; Diagnostic; Disease; Docking; Exhibits; Gene Expression; Genes; HIF1A gene; Hypoxia; MAP Kinase Gene; Mediating; Multivesicular Body; Natural regeneration; Neoplasm Metastasis; Nuclear; Nucleic Acids; Organogenesis; Oxidative Stress; Pathologic; Pathway interactions; Physiological; Play; Process; Production; Proteins; RNA; Regulation; Regulator Genes; Research; Role; Signal Pathway; Sorting; Stress; Therapeutic; Therapeutic Uses; Tissues; Untranslated RNA; Vesicle; Virus Replication; carcinogenesis; disease diagnosis; exosome; extracellular; immune function; immunoregulation; improved; interest; late endosome; macromolecule; nanosized; novel; novel diagnostics; novel marker; novel therapeutics; stem cell differentiation; tissue regeneration; tool; trafficking

SUMMARY Exosomes are nano-sized vesicles secreted into the extracellular milieu by all cells in physiological and pathological states. Exosomes can effectively mediate cell-cell communications, deliver macromolecules such as proteins and nucleic acids to cells, and induce functional changes in recipient cells. Recent studies have implicated that exosomes participate in a broad range of pathophysiological processes, including immune regulation, organogenesis, and carcinogenesis. Despite great interest in exosomes for both diagnostics and therapeutics applications, the basic understanding of the regulation of exosome secretion is not well established. Long noncoding RNAs (lncRNAs), defined as RNAs longer than 200nt without functional protein-coding capacity, are emerging as regulators of gene expression and cellular functions. Our preliminary data has shown that lncRNAs play regulatory roles in exosome biogenesis in both physiologic and cellular stress conditions, such as hypoxia and oxidative stress. How the biogenesis, intracellular trafficking, and cargo soring of the exosomes are regulated by lncRNAs is largely unknown. This project will investigate the role of cytoplasmic and nuclear lncRNAs in exosome biogenesis and identify how they function in the docking, cargo sorting, and fusion of late endosomes or multivesicular bodies to the plasma membrane. The role of lncRNA in the regulation of signaling pathways and genes that regulate different aspects of exosome biogenesis and exosome cargo selection will also be characterized. We will investigate how cellular stress pathways, such as the HIF1-alpha and MAPK pathways, through lncRNA or independent of the lncRNAs, influence exosome biogenesis and cargo selection. Research accomplishments from this project will deepen our understanding of the basic biology of regulation of exosome biogenesis and open new avenues for the therapeutic use of exosomes and lncRNAs in the treatment of various diseases. Exosomes play a vital role in many biological processes, including adaptive immune function, cancer metastasis, the development and differentiation of stem cells, tissue regeneration, and viral replication. They also exhibit profiles specific to the cell of origin and therefore represent novel biomarkers that show promise for improving disease diagnosis. Their central role in cell-to-cell communication presents opportunities for the development of improved therapeutics. Therefore, it is essential to understand the role of lncRNAs in regulating exosome production and release in order to realize these diagnostic and therapeutic opportunities.

总结 外泌体是由生理和生理条件下的所有细胞分泌到细胞外环境中的纳米大小的囊泡。 病理状态。外泌体可以有效地介导细胞-细胞通信，递送大分子，如 作为蛋白质和核酸进入细胞，并诱导受体细胞的功能变化。最近的研究 暗示外泌体参与广泛的病理生理过程，包括免疫 调节、器官形成和致癌作用。尽管对用于诊断和治疗的外来体有很大兴趣， 尽管外泌体在治疗学应用中的应用并不广泛，但对外泌体分泌调节的基本理解还没有很好地建立。 长链非编码RNA（longnoncodingRNAs，lncRNA）是指长度超过200 nt，但没有编码蛋白质功能的RNA， 正在成为基因表达和细胞功能的调节因子。我们的初步数据显示， lncRNA在生理和细胞应激条件下的外泌体生物发生中起调节作用，例如 缺氧和氧化应激。外泌体的生物发生、细胞内运输和货物储存是如何 由lncRNA调控的基因在很大程度上是未知的。本项目将研究细胞质和细胞核的作用 lncRNA在外来体生物发生中的作用，并确定它们如何在后期的对接，货物分选和融合中发挥作用。 内体或多泡体到质膜。 lncRNA在调节信号通路和调节外泌体不同方面的基因中的作用 还将表征生物发生和外来体货物选择。我们将研究细胞压力 途径，如HIF 1-α和MAPK途径，通过lncRNA或独立于lncRNA， 影响外泌体生物发生和货物选择。 该项目的研究成果将加深我们对生物学基础的理解， 外泌体生物发生，并为外泌体和lncRNA在治疗中的治疗用途开辟了新的途径。 各种疾病。外泌体在许多生物学过程中发挥着重要作用，包括适应性免疫 功能，癌症转移，干细胞的发育和分化，组织再生和病毒 复制的它们还表现出对起源细胞特异性的特征，因此代表了新的生物标志物， 显示出改善疾病诊断前景。它们在细胞间通讯中的核心作用 开发改进的治疗方法的机会。因此，了解以下方面的作用至关重要： lncRNA在调节外泌体产生和释放中的作用，以实现这些诊断和治疗 机会