RECOGNITION OF APOPTOTIC AND NECROTIC CELLS BY THEIR PHAGOCYTES

描述（由申请人提供）：在动物发育和成年期间，发生凋亡的细胞通过吞噬作用（吞噬）被其他细胞迅速内化，并在吞噬细胞内降解。死亡细胞的吞噬清除是一个进化保守的过程，具有重要的生理影响。凋亡细胞的清除提供了一种安全的方法来清除体内不需要的和危险的细胞。此外，它还能防止组织损伤、炎症反应和可能由死细胞引起的自身免疫反应。此外，通过坏死死亡的细胞也通过吞噬作用被清除，坏死是另一种形态上不同于细胞凋亡的细胞死亡类型，通常由急性损伤引起。坏死细胞与神经退行性疾病和应激反应有关，清除坏死细胞被认为是组织再生的关键。对死亡细胞清除过程的研究也与癌症的研究和治疗密切相关。我的长期目标是利用秀丽隐杆线虫作为模式生物，了解控制凋亡细胞识别、吞噬和降解的保守分子机制。这个建议的重点是了解通过吞噬细胞来识别死亡细胞，这是死亡细胞移除的第一步。垂死的细胞在其外表面暴露“吃我”信号以吸引吞噬细胞，吞噬细胞利用细胞表面受体识别“吃我”信号并启动吞噬过程。通过吞噬细胞来识别凋亡细胞的机制尚不清楚。关于坏死细胞是如何被识别并从我们的身体中移除的，我们所知道的就更少了。我们之前已经鉴定出秀丽隐杆线虫CED-1是凋亡细胞的吞噬受体。我们进一步发现，磷脂酰丝氨酸（PS）是一种质膜磷脂，暴露在凋亡细胞的外表面，作为吸引CED-1的“吃我”信号。本项目旨在研究凋亡和坏死细胞暴露于PS的分子机制，以及CED-1和潜在的CED-1共受体对PS的识别。我们的工作将确定共同的和不同的机制，控制吞噬细胞识别坏死和凋亡细胞，死亡的不同机制。此外，我们的工作将揭示细胞死亡和清除过程中细胞-细胞识别和受体激活的新机制。

DESCRIPTION (provided by applicant): During animal development and in adulthood, cells undergoing apoptosis are rapidly internalized by other cells via phagocytosis (engulfment) and degraded inside phagocytes. The phagocytic removal of dying cells is an evolutionarily conserved process that has important physiological impact. 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. In addition, cells that die through necrosis, another type of cell death morphologically distinct from apoptosis and frequently caused by acute injury are also removed via phagocytosis. The removal of necrotic cells, which are associated with neurodegenerative disorders and stress responses, is considered critical for tissue regeneration. The study of the dying-cell removal process is also closely related to cancer research and treatment. My long-term objective is to understand the conserved molecular mechanism that controls the recognition, engulfment, and degradation of apoptotic cells, using the nematode Caenorhabditis elegans as a model organism. This proposal focuses on understanding the recognition of dying cells by engulfing cells, the first step of dying- cell removal. Dying cells expose "eat me" signal(s) on their outer surfaces to attract engulfing cells, which use cell-surface receptors to recognize the "eat me" signal(s) and initiate the engulfment process. A lot remains unknown about the mechanism that leads to the recognition of apoptotic cells by engulfing cells. Even less is known about how necrotic cells are recognized and removed from our bodies. We have previously identified C. elegans CED-1 as a phagocytic receptor for apoptotic cells. We have further found that phosphatidylserine (PS), a plasma membrane phospholipid, which is exposed on the outer surfaces of apoptotic cells, act as an "eat me" signal that attracts CED-1. This project investigates the molecular mechanisms leading to the exposure of PS by apoptotic and necrotic cells and the recognition of PS by CED-1 and a potential co-receptor of CED-1. Our work will identify common and different mechanisms that control the phagocytic recognition of necrotic and apoptotic cells, which die of different mechanisms. Furthermore, our work will shed light on novel mechanisms of cell-cell recognition and receptor activation during cell death and clearance.