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.

抽象的： 巨胞饮体是相对较大的内吞性囊泡，几乎在所有生长中形成 后生动物细胞通过质膜和肌动蛋白细胞骨架的运动， 通过微管依赖性膜融合将细胞外溶质递送至溶酶体 反应。巨胞饮作用是许多致病细菌和病毒侵入的途径 宿主细胞，采集抗原以启动免疫反应，并获取细胞外营养物质 摄入以支持 K-Ras 转化的癌细胞的生长。斯旺森实验室的研究 介绍了巨胞饮作用的基本概念，包括膜如何 磷脂修饰酶和细胞骨架活性协调巨脂质体 形成，巨脂质体如何将生长信号从细胞表面受体传递到 雷帕霉素复合物-1 (mTORC1) 在溶酶体膜上的机制靶标，以及如何 巨胞饮作用限制了活化巨噬细胞中溶酶体膜的损伤。尽管 人们认识到巨胞饮作用在健康和疾病中的重要性，以及相当大的影响 在理解其机制和监管方面取得进展，但仍然存在重大问题 未解答：（1）1型磷脂酰肌醇3-激酶如何组织巨胞饮杯 封闭成大脂质体？ (2) Src家族激酶如何调节巨胞饮作用？ (3) 哪些分子或活动决定巨脂质体是否输送其溶质内容物 进入溶酶体还是将它们回收到细胞表面？ (4)细胞营养状况如何 通过巨胞饮作用影响溶质积累？该研究计划采用创新 细胞生物学、分子遗传学和定量显微镜的方法来回答这些问题 基本问题。这项研究的继续将把巨胞饮作用纳入 细胞生长、代谢和先天免疫的背景，并可能导致新的治疗方法 治疗癌症、传染病和免疫系统疾病的方法。