Molecular Basis and Regulatory Mechanisms of Exosome Secretion

外泌体分泌的分子基础和调控机制

基本信息

批准号：
10397628
负责人：
WEI GUO
金额：
$ 62.09万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10397628
关键词：
Address Affect Behavior Biochemistry Biogenesis Biological Cancer Biology Cardiovascular system Cell Communication Cell membrane Cells Cellular biology Complex Development Docking Encapsulated Endosomes Family Foundations Goals Immune Evasion Immune system Immunobiology Immunosuppression Lipids Malignant Neoplasms Mediating Metastasis Suppression MicroRNAs Microtubules Mitogen-Activated Protein Kinases Molecular Monomeric GTP-Binding Proteins Motor Multivesicular Body Nerve Degeneration Oncogenic Organogenesis Process Proteins Research Signal Pathway Signal Transduction Signaling Molecule Signaling Protein Tumor Biology Tumor-Associated Process Vesicle Viral Work cancer diagnosis cancer therapy endosome membrane exosome extracellular extracellular vesicles interdisciplinary approach interest neoplastic cell novel pathogen therapeutic target trafficking tumor tumor growth tumor microenvironment tumor progression

项目摘要

ABSTRACT Exosomes are lipid-encapsulated small vesicles secreted by cells to the extracellular milieu, and are recently recognized as a novel and highly effective means of cell-cell communication. Exosomes carry bioactive molecules such as signaling proteins and microRNAs that potently affect the behavior and function of their recipient cells. Studies in recent years have implicated the exosomes in a wide range of pathophysiological processes such as organogenesis, viral propagation, tumor metastasis and immune suppression. Despite the great interest in exosomes in various fields, the basic cell biological understanding of exosomes is disproportionally lacking. The biogenesis of exosomes starts when the limiting membrane of endosomes invaginates to form intraluminal vesicles (ILVs). These endosomes, called multivesicular bodies (MVBs), are then transported to the cell periphery for the release of the ILVs–the exosomes. While the biogenesis of MVBs is mostly mediated by the ESCRT complex, the molecular machinery that mediates the transport of MVBs to the cell periphery, and their subsequent docking and fusion with the plasma membrane for exosome release, remains elusive. In addition, how the biogenesis and intracellular trafficking of the exosomes are regulated by signaling molecules is largely unknown. The goal of our research is to identify the basic machinery that mediating the intracellular trafficking of the exosomes, and to elucidate how oncogenic signaling control these processes for tumor progression. First, we will study several classes of proteins including the Rab family of small GTPases, the octameric exocyst complex, and microtubule motor proteins, and understand how they function in concert in the transport, docking and fusion of MVBs to the plasma membrane. These work will lay the foundation for the basic cell biological understanding of exosome secretion. Second, we will identify and characterize oncogenic signaling pathways that regulate various aspects of exosome trafficking, from exosome protein cargo selection, to exosome release at the plasma membrane. At the functional level, we will study how tumor cell-intrinsic signaling pathways such as the Mitogen- Activated Protein Kinase (MAPK) axis, through the exosomes, influence tumor microenvironment and the immune system to promote tumor growth and immune evasion. A multidisciplinary approach that combines biochemistry, cell biology, tumor biology, and immunobiology will be taken to address these questions. Our study will bridge basic exosome cell biology to cancer biology. It will not only lay the cell biological foundation for the molecular and mechanistic understanding of exosomes, but also open new venues for therapeutic targeting of exosomes in cancer.

抽象的外泌体是由细胞分泌到细胞外环境的脂质包裹的小囊泡，最近被研究外泌体被认为是一种新颖且高效的细胞间通讯方式，携带生物活性分子。例如信号蛋白和 microRNA，它们可以有效影响受体细胞的行为和功能。近年来的研究表明外泌体与多种病理生理过程有关，例如尽管人们对器官发生、病毒传播、肿瘤转移和免疫抑制非常感兴趣。外泌体在各个领域都有应用，但对外泌体的基本细胞生物学理解却非常缺乏。当内体的限制膜内陷形成管腔内时，外泌体的生物发生开始这些内体被称为多囊泡体 (MVB)，然后被转运到细胞外周。 ILV 的释放——外泌体，而 MVB 的生物发生主要是由 ESCRT 介导的。复杂的分子机制，介导 MVB 向细胞外周的运输，以及随后的过程此外，如何与质膜对接和融合以释放外泌体，仍然是一个难以捉摸的问题。外泌体的生物发生和细胞内运输受信号分子调节尚不清楚。我们研究的目标是确定介导细胞内转运的基本机制外泌体，并阐明致癌信号如何控制这些肿瘤进展过程。研究几类蛋白质，包括小 GTP 酶的 Rab 家族、八聚体外囊复合物，以及微管运动蛋白，并了解它们如何在转运、对接和融合中协同发挥作用这些工作将为细胞生物学的基本理解奠定基础。其次，我们将识别和表征调节各种致癌信号通路。外泌体运输的各个方面，从外泌体蛋白质货物选择到血浆中的外泌体释放在功能水平上，我们将研究肿瘤细胞内在信号通路（例如丝裂原）如何发挥作用。激活蛋白激酶（MAPK）轴，通过外泌体，影响肿瘤微环境和免疫系统促进肿瘤生长和免疫逃避的系统，结合了生物化学、我们的研究将利用细胞生物学、肿瘤生物学和免疫生物学来解决这些问题。基础外泌体细胞生物学到癌症生物学不仅为分子生物学奠定了细胞生物学基础。和对外泌体机制的理解，同时也为外泌体的治疗靶向开辟了新的场所癌症。