Recognition of Apoptotic Cells for Their Phagocytosis

描述(申请人提供)：我研究的长期目标是了解控制动物体内凋亡细胞识别和吞噬去除的机制。在动物的发育和成体过程中，经历细胞凋亡的细胞，即细胞自杀过程，通过吞噬过程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、炎症和自身免疫反应的预防和消退以及组织损伤的修复都很重要。这项提议旨在揭示线虫体内吞噬细胞是如何识别凋亡细胞的。特别是，它建议调查凋亡的线虫细胞如何产生并在其外表面呈现Eat Me信号(S)，以及我之前的研究发现的一种吞噬细胞表面受体CED-1如何识别“Eat Me”信号(S)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类似的配体结合特异性。磷脂酰丝氨酸(PS)是一种磷脂，通过对哺乳动物细胞培养和我对线虫的研究，已经发现它是吞噬作用的候选信号。特定目的1建议通过缺失和突变分析来剖析CED-1胞外区的功能，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聚集在凋亡细胞周围。特定目的2建议研究CED-7的功能，CED-7是线虫的哺乳动物ABC(三磷酸腺苷结合盒)转运蛋白的同源物。CED-1识别凋亡细胞需要CED-7功能。CED-7是否作用于细胞凋亡或吞噬细胞以实现这一功能，此外，CED-7是否提供吞噬信号(S)将被研究。具体目标3建议通过基因分析识别CED-1识别凋亡细胞所需的基因。对这些基因的研究将确定Eat Me信号(S)及其产生和呈现所需的分子，以及帮助CED-1作为Eat Me信号受体的分子(S)。在未来，这些线虫基因将帮助我们识别和了解它们的哺乳动物同行在清除凋亡细胞方面的功能。

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.