The Regulation of Macropinocytosis

巨胞饮作用的调节

• 批准号: 9893006
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9893006
• 关键词: 1-Phosphatidylinositol 3-Kinase; 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; Foundations; Growth; Health; Human; Immune System Diseases; Immune response; Ingestion; Invaded; KRAS2 gene; Lead; Lysosomes; Malignant Neoplasms; Membrane; Membrane Fusion; Metabolism; Microtubules; Molecular Genetics; Natural Immunity; Nutrient; Phospholipids; Quantitative Microscopy; Reaction; Regulation; Research; Route; Sampling; Signal Transduction; Vesicle; cancer cell; cell growth; cell motility; extracellular; innovation; macrophage; novel therapeutic intervention; pathogenic bacteria; pathogenic virus; programs; solute; src-Family Kinases

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： 大氨基粒子是相对较大的内吞囊泡，几乎在所有生长中形成 通过质膜和肌动蛋白细胞骨架的运动，内唑细胞，以及 通过微管依赖性膜融合，将细胞外溶质输送到溶酶体中 反应。大型细胞增多症是许多致病细菌和病毒入侵的途径 宿主细胞，采样抗原以开始免疫反应，细胞外营养素为 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 已经引入了有关大型细胞增多症的基础概念，包括膜如何 磷脂修改酶和细胞骨架活性坐标大斑粒子体 形成，大型体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）在溶酶体膜上的机理靶标，以及如何 大型细胞增多症限制了活化巨噬细胞中溶酶体膜的损害。尽管 大型细胞增多症在健康和疾病中的认识重要性以及相当大的 了解其机制和监管的进展，仍然存在重大问题 未解决：（1）1型1型磷脂酰肌醇3-激酶如何组织大型细胞杯 闭合成大斑粒子？ （2）SRC家庭激酶如何调节大型细胞增多症？ （3） 哪些分子或活性决定了大肺化体是否提供其溶质含量 进入溶酶体或将其回收到细胞表面？ （4）细胞营养状况如何 影响大型细胞增多症的溶质积累？该研究计划使用创新 细胞生物学，分子遗传学和定量显微镜的方法来回答这些 基本问题。这项研究的继续将大量细胞增多症进入 细胞生长，代谢和先天免疫的背景，并可能导致新的治疗 免疫系统的癌症，传染病和疾病的方法。