Recognition of Apoptotic Cells for Their Phagocytosis

描述（由申请人提供）：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清除的机制。在动物的发育和成年期，经历细胞凋亡（细胞自杀过程）的细胞通过吞噬作用迅速内化到其他细胞内，并迅速降解。凋亡细胞的吞噬作用是一个进化上保守的过程，在健康中起着关键作用。它对于组织重塑、预防和解决炎症和自身免疫反应以及修复组织损伤非常重要。本研究旨在揭示线虫C. elegans识别凋亡细胞。特别是，它建议调查如何凋亡C。elegans细胞产生并在其外表面上呈现吃我信号，以及CED-1，一种吞噬细胞表面受体，如何识别“吃我”信号并激活吞噬。CED-1类似于来自内皮细胞的哺乳动物清道夫受体（SREC），并且可能具有类似于清道夫受体的配体结合特异性。磷脂酰丝氨酸（PS）是一种磷脂，在哺乳动物细胞培养中的研究和我在C.优雅具体目标1提出通过缺失和突变分析来剖析CED-1的胞外结构域的功能，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聚集在凋亡细胞周围。具体目标2提出研究C.哺乳动物ABC（ATP结合盒）转运蛋白的elegans同源物。CED-1需要CED-7功能来识别凋亡细胞。将检查CED-7是否在凋亡细胞或吞噬细胞中起作用以实现该功能，以及CED-7是否起作用以呈现进食信号。具体目标3提出通过遗传分析鉴定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，以及帮助CED-1作为“吃我”信号受体的分子。在未来，这些C。elegans的基因将帮助我们识别和理解哺乳动物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.