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RECOGNITION OF APOPTOTIC AND NECROTIC CELLS BY THEIR PHAGOCYTES

吞噬细胞对凋亡和坏死细胞的识别

基本信息

批准号：
9244036
负责人：
Zheng Zhou
金额：
$ 29.74万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-10 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9244036
关键词：
ATP-Binding Cassette Transporters Acute Adult Affect Animal Model Animals Apoptosis Apoptotic Area Autoimmune Diseases Belief Biological Models Caenorhabditis elegans Cell Death Cell Surface Receptors Cell membrane Cells Cessation of life Chronic Complex Dangerousness Development Digestion Eating Event Excision Exposure to Genes Homologous Gene Human Immune response In Vitro Inflammatory Inflammatory Response Injury Integral Membrane Protein Laboratories Learning Left Light Molecular Morphology Mus Mutation Necrosis Nematoda Nerve Degeneration Neurodegenerative Disorders Pathologic Pathway interactions Pattern Phagocytes Phagocytosis Phosphatidylserines Phospholipids Physiological Play Process Receptor Activation Resolution Role Signal Transduction Stroke Surface Therapeutic Tissues Translating Work accomplished suicide anticancer research biological adaptation to stress cancer cell cancer therapy cell injury cell type fighting mutant novel phospholipid scramblase prevent public health relevance receptor tissue regeneration wound

项目摘要

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.

描述（申请人提供）：在动物发育和成年期间，经历凋亡的细胞通过吞噬作用（吞噬）被其他细胞快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上保守的过程，具有重要的生理影响。去除凋亡细胞为消除体内不需要的和危险的细胞提供了一种安全的方法。此外，它还可以防止死细胞内容物引起的组织损伤、炎症反应和自身免疫反应。此外，通过坏死而死亡的细胞，这是另一种形态上与细胞凋亡不同的细胞死亡类型，通常由急性损伤引起，也通过吞噬作用被清除。坏死细胞的清除与神经退行性疾病和应激反应相关，被认为对于组织再生至关重要。垂死细胞清除过程的研究也与癌症研究和治疗密切相关。我的长期目标是使用线虫秀丽隐杆线虫作为模式生物，了解控制凋亡细胞的识别、吞噬和降解的保守分子机制。该提案的重点是了解吞噬细胞对垂死细胞的识别，这是去除垂死细胞的第一步。垂死细胞在其外表面暴露“吃我”信号以吸引吞噬细胞，吞噬细胞使用细胞表面受体识别“吃我”信号并启动吞噬过程。关于通过吞噬细胞来识别凋亡细胞的机制仍有很多未知之处。关于坏死细胞是如何被识别并从我们的身体中清除的，我们知之甚少。我们之前已将线虫 CED-1 鉴定为凋亡细胞的吞噬细胞受体。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，充当吸引CED-1的“吃我”信号。该项目研究导致凋亡和坏死细胞暴露 PS 以及 CED-1 和 CED-1 潜在共受体识别 PS 的分子机制。我们的工作将确定控制坏死和凋亡细胞吞噬识别的常见和不同机制，这些细胞死于不同的机制。此外，我们的工作将揭示细胞死亡和清除过程中细胞间识别和受体激活的新机制。