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.

摘要 外切体是由所有细胞在生理和生理状态下分泌到细胞外环境中的纳米大小的囊泡。 病态。胞外体可以有效地介导细胞间的通讯，传递大分子，如 以蛋白质和核酸的形式进入细胞，并诱导受体细胞的功能变化。最近的研究表明 暗示外切体参与广泛的病理生理过程，包括免疫 调节、器官发生和致癌。尽管人们对外显体在诊断和治疗方面都很感兴趣 在治疗应用方面，对外切体分泌调节的基本认识还不是很清楚。 长非编码RNAs(LncRNAs)，定义为长度超过200nT但没有功能性蛋白质编码能力的RNAs， 正在成为基因表达和细胞功能的调节者。我们的初步数据显示， 在生理和细胞应激条件下，lncRNAs在外切体的生物发生中发挥调节作用，例如 缺氧和氧化应激。外切体的生物发生、细胞内运输和货物分拣是如何 受lncRNAs调控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。 LncRNAs在外体生物发生中的作用，并确定它们在后期对接、货物分拣和融合中的作用 内体或多囊泡体至质膜。 LncRNA在调控外切体不同方面的信号通路和基因中的作用 生物发生和外显体货物的选择也将被描述。我们将研究细胞压力是如何 途径，如HIF1-α和MAPK途径，通过lncRNA或不依赖于lncRNA， 影响外切体的生物发生和货物选择。 这个项目的研究成果将加深我们对调控的基本生物学的理解。 外切体的生物发生及外切体和lncRNA在治疗中的应用 各种疾病。外切体在许多生物过程中起着至关重要的作用，包括获得性免疫。 功能、癌症转移、干细胞的发展和分化、组织再生和病毒 复制。它们还展示了起源细胞特有的特征，因此代表了新的生物标志物 显示出改善疾病诊断的希望。它们在细胞间通讯中的中心作用呈现 发展改良疗法的机会。因此，有必要了解 LncRNAs调控外切体的产生和释放，从而实现这些诊断和治疗 机遇。