Degradation of dying cells

项目摘要 本项目研究凋亡细胞被吞噬细胞内化后的降解。期间 动物的发育和成年期，细胞经历凋亡，这是动物生长和发育所必需的细胞死亡过程。 发育和稳态，通过吞噬作用（吞噬）被其他细胞迅速内化， 在吞噬细胞内降解凋亡细胞的去除提供了一种安全的方法， 有害和危险的细胞。此外，它还能防止组织损伤，炎症反应， 以及由死细胞内容物诱导的自身免疫反应。反渗透细胞的研究 去除也激发了新的癌症治疗策略的发展。考虑到强大的进化 发展机制的保守性，我们从C. elegans将被翻译成人类。我 长期目标是了解控制识别，吞噬和 凋亡细胞的降解，使用线虫秀丽隐杆线虫作为模式生物。 这个项目集中在两个方面的重要降解吞噬凋亡细胞，这是 被限制在称为“吞噬体”的空泡结构中。吞噬体经历一个“成熟”过程， 一系列膜运输事件，导致多种类型的细胞内 细胞器进入吞噬体和消化酶沉积到吞噬体腔。结果是 吞噬体内的货物被消化，被消化的物质和吞噬体膜被输出， 吞噬体被分解。关于吞噬体的降解，还有许多问题尚未探讨。 我们的研究将建立一个新的自噬和吞噬作用之间的功能关系（目的1和2）。 特别是，我们将证明自噬体，这是双膜细胞内的细胞器， 其主要作用是清除细胞聚集体和无活性的大分子复合物和细胞器， 被募集到吞噬体表面并与吞噬体融合的新型细胞器（目的1）。我们将 进一步探讨自噬体和吞噬体之间的融合是否是一个保守的事件， 哺乳动物（目标2）。在一个单独的项目中，我们将研究两种建议的调节机制， “吞噬体分解”，完成降解和吞噬体内容物的输出（目标3）。的 提出的工作将在揭示细胞内信号转导和膜的新机制产生广泛的影响， 这对动物的发展至关重要。

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.