Recognition of Apoptotic Cells for Their Phagocytosis

描述（由申请人提供）：我的长期研究目标是了解动物体内凋亡细胞的识别和吞噬清除的控制机制。在动物的发育和成年过程中，细胞凋亡（一种细胞自杀过程）通过吞噬作用迅速内化到其他细胞中，并迅速降解。凋亡细胞的吞噬作用是一个进化保守的过程，在健康中起着关键作用。它对组织重塑、预防和解决炎症和自身免疫反应以及组织损伤的修复具有重要作用。本研究旨在揭示线虫的吞噬细胞如何识别凋亡细胞。特别是，本研究提出研究凋亡的秀丽隐杆线虫细胞如何产生并在其外表面呈现“吃我”信号，以及我之前研究发现的吞噬细胞表面受体CED-1如何识别“吃我”信号并激活吞噬。CED-1类似于哺乳动物内皮细胞清道夫受体（SREC），可能具有与清道夫受体相似的配体结合特异性。磷脂酰丝氨酸（PS）是一种磷脂，在哺乳动物细胞培养和我对秀丽隐杆线虫的研究中被认为是吞噬作用的候选“吃掉我”信号。Specific Aim 1提出通过缺失和突变分析来剖析CED-1胞外结构域的功能，旨在了解CED-1如何与凋亡细胞结合，以及这种结合如何诱导膜结合的CED-1在凋亡细胞周围聚集。Specific Aim 2提出研究线虫中与哺乳动物ABC （atp结合盒）转运体同源的CED-7的功能。CED-1识别凋亡细胞需要CED-7的功能。我们将研究CED-7是否在凋亡细胞或吞噬细胞中发挥这一作用，并进一步研究CED-7是否起到“吃我”信号的作用。Specific Aim 3提出通过遗传分析来鉴定CED-1识别凋亡细胞所需的基因。对这些基因的研究将确定“吃我”信号及其产生和呈现所需的分子，以及协助CED-1作为“吃我”信号受体发挥作用的分子。在未来，这些秀丽隐杆线虫基因将帮助我们识别和了解它们的哺乳动物对应物在清除凋亡细胞中的功能。

DESCRIPTION (provided by applicant): The long-term goal of my research is to understand the mechanisms that control the recognition and phagocytic removal of apoptotic cells inside animal bodies. During an animal's development and adulthood, cells undergoing apoptosis, a cell suicide process, are rapidly internalized inside other cells via the process of phagocytosis, and are quickly degraded. Phagocytosis of apoptotic cells is an evolutionarily conserved process that plays pivotal roles in health. It is important for tissue remodeling, prevention and resolution of inflammatory and autoimmune responses, and repair of tissue injury. This proposal aims at revealing how engulfing cells in the nematode C. elegans recognizes apoptotic cells. In particular, it proposes to investigate how apoptotic C. elegans cells generate and present eat me signal(s) onto their outer surfaces, and how CED-1, an engulfing cell surface receptor identified by my previous research, recognizes the "eat me" signal(s) and activates engulfment. CED-1 is similar to mammalian Scavenger Receptor from Endothelial Cells (SREC) and may possess ligand-binding specificities similar to that of scavenger receptors. Phosphatidylserine (PS), a phospholipid, has been implicated as a candidate "eat me" signal for phagocytosis by studies in mammalian cell culture and by my research in C. elegans. Specific Aim 1 proposes to dissect the functions of the extracellular domain of CED-1 by deletional and mutational analyses, aiming at learning how CED-1 binds to apoptotic cells and how this binding induces membrane bound CED-1 to cluster around apoptotic cells. Specific Aim 2 proposes to study the function of CED-7, a C. elegans homolog of mammalian ABC (ATP-binding cassette) transporters. CED-7 function is required for CED-1 to recognize apoptotic cells. Whether CED-7 acts in the apoptotic or engulfing cells for this function and furthermore, whether CED-7 acts to present the eat me signal(s) will be examined. Specific Aim 3 proposes to identify genes required for CED-1 to recognize apoptotic cells through genetic analyses. Studies of such genes will identify the eat me signal(s) and molecules required for its generation and presentation, and molecules that assist CED-1 to function as a receptor for the eat me signal(s). In the future, these C. elegans genes will help us identify and understand the functions of their mammalian counterparts in the clearance of apoptotic cells.