The Regulation of Macropinocytosis

巨胞饮作用的调节

• 批准号: 10598550
• 负责人: JOEL A SWANSON
• 金额: $ 45.87万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10598550
• 关键词: Actins; Antigens; Cell Surface Receptors; Cell membrane; Cell surface; Cells; Cellular Metabolic Process; Cellular biology; Communicable Diseases; Complex; Cytoskeleton; Disease; Endocytic Vesicle; Enzymes; Extracellular Fluid; FRAP1 gene; Growth; Health; Human; Immune System Diseases; Immune response; Ingestion; Invaded; KRAS2 gene; Lysosomes; Macrophage; Malignant Neoplasms; Membrane; Membrane Fusion; Metabolism; Microtubules; Molecular Genetics; Natural Immunity; Nutrient; PIK3CG gene; Phospholipids; Quantitative Microscopy; Reaction; Recycling; Regulation; Research; Route; Sampling; Signal Transduction; Vesicle; cancer cell; cell growth; cell motility; extracellular; innovation; novel therapeutic intervention; pathogenic bacteria; pathogenic virus; programs; solute; src-Family Kinases; transmission process

Abstract: Macropinosomes are relatively large endocytic vesicles which form in nearly all growing metazoan cells by movements of plasma membrane and the actin cytoskeleton, and which deliver extracellular solutes into lysosomes by microtubule-dependent membrane fusion reactions. Macropinocytosis is the route by which many pathogenic bacteria and viruses invade host cells, antigen is sampled for initiation of immune responses, and extracellular nutrients are ingested to support the growth of K-Ras-transformed cancer cells. Research in the Swanson lab has introduced foundational concepts about macropinocytosis, including how membrane phospholipid-modifying enzymes and cytoskeletal activities coordinate macropinosome formation, how macropinosomes transmit growth signals from cell surface receptors to the mechanistic target of rapamycin complex-1 (mTORC1) on lysosomal membranes, and how macropinocytosis limits damage to lysosomal membranes in activated macrophages. Despite the recognized importance of macropinocytosis in health and disease, and the considerable progress in understanding its mechanism and regulation, significant questions remain unanswered: (1) How does type 1 phosphatidylinositol 3-kinase organize macropinocytic cup closure into macropinosomes? (2) How do Src-family kinases regulate macropinocytosis? (3) What molecules or activities determine whether macropinosomes deliver their solute contents into lysosomes or recycle them to the cell surface? (4) How does cellular nutrient status influence solute accumulation by macropinocytosis? This research program uses innovative approaches to cell biology, molecular genetics and quantitative microscopy to answer these fundamental questions. The continuation of this research will put macropinocytosis into the context of cell growth, metabolism and innate immunity, and could lead to new therapeutic approaches to cancer, infectious diseases and disorders of the immune system.

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