Phagocytic Removal of Apoptotic Cells

描述（由申请人提供）：在动物发育和成年期间，细胞经历凋亡，这是动物发育和体内平衡所必需的细胞死亡过程，通过吞噬（吞噬）被其他细胞迅速内化并在吞噬细胞内降解。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。凋亡细胞去除的研究也激发了新的癌症治疗策略的发展。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、吞噬和降解的分子机制。我们相信，从秀丽隐杆线虫身上学到的东西将被转化为人类。这些项目研究驱动凋亡细胞降解的机制，这些细胞被内化到宿主细胞中，被限制在一个被称为“吞噬体”的液泡结构中。吞噬体通过一系列膜运输事件经历“成熟”过程，最终结果是管腔内的货物降解。我们的研究将揭示磷脂酰肌醇3-磷酸（PI3P）的产生（Aim 1）和周转（Aim 2）的时间调控机制，PI3P是一种脂质第二信使，在启动吞噬体成熟过程中起重要作用，以及PI3P如何触发成熟过程（Aims 3）。我们对PI3P信号传导机制的研究不仅将揭示凋亡细胞的降解，还将广泛地揭示其他PI3P介导的膜运输事件背后的分子机制，包括内吞运输和自噬。

DESCRIPTION (provided by applicant): 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. 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. We believe that what is learnt from C. elegans will be translated to humans. These project studies mechanisms that drive the degradation of apoptotic cells, which are internalized into host cells, confined in a vacuolar structure called "phagosome". Phagosomes undergo a "maturation" process through a series of membrane trafficking events and the end result is the degradation of cargos in the lumen. Our studies will reveal the temporal regulation mechanisms of the production (Aim 1) and turnover (Aim 2) of phosphatidylinositol 3-phosphate (PI3P), a lipid second messenger that plays an essential role in initiating phagosome maturation, on phagosomes, and how PI3P triggers the maturation process (Aims 3). Our study of the PI3P signaling mechanisms will shed light not only on the degradation of apoptotic cells, but also broadly, on the molecular mechanisms behind other PI3P-mediated membrane trafficking events, including endocytic trafficking and autophagy. PUBLIC HEALTH RELEVANCE: This project studies how apoptotic cells (cells that commit suicide) generated in animal bodies are engulfed and digested by other cells, a process that protects humans from the harmful inflammatory and auto-immune responses that apoptotic cells would induce if they are left in the body. Understanding the mechanisms controlling this process will have important therapeutic implications, in fighting chronic inflammatory and auto- immune diseases, and in developing new strategies to remove cancer cells through engulfment and digestion.