Degradation of dying cells

垂死细胞的降解

• 批准号: 9917792
• 负责人: Zheng Zhou
• 金额: $ 35.51万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9917792
• 关键词: 1-Phosphatidylinositol 3-Kinase; Adult; Affect; Animal Model; Animals; Apoptosis; Apoptotic; Autoimmune Diseases; Autoimmune Responses; Autophagocytosis; Autophagosome; Caenorhabditis elegans; Carrier Proteins; Cell Death Process; Cell physiology; Cells; Chronic; Complex; Cytoplasm; Dangerousness; Deposition; Development; Developmental Process; Digestion; Docking; Early Endosome; Eating; Embryo; Enzymes; Event; Excision; Funding; Genes; Genetic Screening; Goals; Homeostasis; Human; Humulus; Inflammatory; Inflammatory Response; Injury; Intracellular Membranes; Lead; Learning; Lipids; Lysosomes; Mammals; Membrane; Molecular; Monitor; Monomeric GTP-Binding Proteins; Mutation; Names; Nature; Necrosis; Nematoda; Organelles; Pathway interactions; Phagocytes; Phagocytosis; Phagosomes; Phenotype; Phosphatidylinositols; Process; Proteins; Protocols documentation; Recycling; Regulation; Research; Resolution; Role; Series; Signal Pathway; Signal Transduction; Structure; Surface; Therapeutic; Translating; Vesicle; Work; accomplished suicide; cancer cell; cancer therapy; fighting; macromolecule; microscopic imaging; mutant; novel; particle; prevent; protein function; rab GTP-Binding Proteins; receptor; recruit; tissue injury; tool; trafficking; treatment strategy

Project Summary This project studies the degradation of apoptotic cells after they are internalized into phagocytes. During animal development and adulthood, cells undergoing apoptosis, a cell death process essential for animal development and homeostasis, are rapidly internalized by other cells via phagocytosis (engulfment) and degraded inside engulfing cells. The removal of apoptotic cells provides a safe means for eliminating unwanted and dangerous cells from the body. Furthermore, it prevents tissue injury, inflammatory responses, and auto-immune responses that could be induced by the content of dead cells. The study of apoptotic-cell removal has also inspired the development of novel cancer treatment strategies. Given the strong evolutionary conservation of developmental mechanisms, what we learn from C. elegans will be translated to humans. My long-term objective is to understand the molecular mechanism that controls the recognition, engulfment, and degradation of apoptotic cells, using the nematode Caenorhabditis elegans as a model organism. This project focuses on two aspects important for the degradation of the engulfed apoptotic cells, which are confined in a vacuolar structure called a “phagosome”. Phagosomes undergo a “maturation” process through a series of membrane trafficking events that lead to the incorporation of multiple types of intracellular organelles into phagosomes and the deposition of digestive enzymes into phagosomal lumen. As a result the cargo inside a phagosome is digested, the digested substances and the phagosomal membrane are exported, and a phagosome is resolved. Many questions remain unexplored regarding the degradation of a phagosome. Our studies will establish a novel functional relationship between autophagy and phagocytosis (Aims 1 and 2). In particular, we will demonstrate that autophagosomes, which are double-membrane intracellular organelles whose primary role is to clear cellular aggregates and inactive macromolecule complexes and organelles, is a new kind of organelles that are recruited to phagosomal surface and fuse with phagosomes (Aim 1). We will further explore whether the fusion between autophagosomes and phagosomes is a conserved event in mammals (Aim 2). In a separate project, we will investigate two propose mechanisms that regulate “phagosome resolution”, the completion of degradation and the export of phagosomal contents (Aim 3). The proposed work will have broad impact in revealing novel mechanisms of intracellular signaling and membrane trafficking, which are essential for animal development.

项目摘要 这个项目研究了凋亡细胞内化成吞噬细胞后的降解。在.期间 动物发育和成体，细胞发生凋亡，这是动物必不可少的细胞死亡过程 发育和动态平衡，通过吞噬作用(吞噬)被其他细胞迅速内化 在吞噬细胞内降解。清除凋亡细胞提供了一种安全的方法 体内多余和危险的细胞。此外，它还可以防止组织损伤、炎症反应、 以及可以由死亡细胞含量诱导的自身免疫反应。细胞凋亡的研究进展 切除也启发了新的癌症治疗策略的发展。考虑到强大的进化能力 为了保护发育机制，我们从线虫身上学到的东西将被移植到人类身上。我的 长期目标是了解控制识别、吞噬和 以线虫秀丽线虫为模式生物，研究凋亡细胞的降解。 这个项目集中在两个对被吞噬的凋亡细胞的降解很重要的方面，这两个方面是 被限制在一个叫做“吞噬小体”的空泡结构中。吞噬小体通过以下途径经历“成熟”过程 导致多种类型细胞内结合的一系列膜转运事件 细胞器进入吞噬小体，消化酶沉积到吞噬小体的腔内。因此， 吞噬体内的货物被消化，消化的物质和吞噬体膜被输出， 吞噬小体就被分解了。关于吞噬小体的降解，仍有许多问题未被探索。 我们的研究将在自噬和吞噬之间建立一种新的功能关系(目标1和2)。 特别是，我们将证明自噬小体，即双膜细胞内细胞器 其主要作用是清除细胞聚集体和不活跃的大分子复合体和细胞器 被募集到吞噬小体表面并与吞噬小体融合的新型细胞器(目标1)。我们会 进一步探讨自噬小体和吞噬小体之间的融合是否是一种保守事件 哺乳动物(目标2)。在另一个单独项目中，我们将调查两个提出的监管机制 “吞噬小体分解”、完成降解和输出吞噬小体内容物(目标3)。这个 拟议的工作将在揭示细胞内信号和膜的新机制方面产生广泛的影响 贩运，这对动物发展是必不可少的。