Molecular Basis and Regulatory Mechanisms of Exosome Secretion

外泌体分泌的分子基础和调控机制

• 批准号: 10205398
• 负责人: WEI GUO
• 金额: $ 50.73万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 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/10205398
• 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

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.

摘要