Phagocytic Removal of Apoptotic and Necrotic Cells

吞噬去除凋亡和坏死细胞

• 批准号: 7526945
• 负责人: Zheng Zhou
• 金额: $ 33万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7526945
• 关键词: 1-Phosphatidylinositol 3-Kinase; ATP-Binding Cassette Transporters; Animal Model; Animals; Apoptosis; Apoptotic; Award; Belief; Biological; Biological Models; Caenorhabditis elegans; Caspase; Cell Communication; Cell Death; Cells; Class; Complex; Defect; Development; Dynamin; Eating; Event; Excision; Genes; Guanosine Triphosphate Phosphohydrolases; Human; Human body; Immune System Diseases; Immune response; Inflammatory; Inflammatory Response; Injury; Integral Membrane Protein; Investigation; Knowledge; Learning; Light; Localized; Mammals; Mediator of activation protein; Molecular; Monomeric GTP-Binding Proteins; Necrosis; Nematoda; Neurodegenerative Disorders; Neurons; Orthologous Gene; PH Domain; Pathway interactions; Personal Satisfaction; Phagocytes; Phagocytosis; Phagosomes; Phosphatidylinositols; Phosphatidylserines; Phosphoinositide-3-Kinase, Catalytic, Gamma Polypeptide; Play; Process; Production; Proteins; Pseudopodia; Public Health; Recruitment Activity; Research; Role; Signal Transduction; Surface; System; Testing; Therapeutic; Tissues; Touch sensation; Translating; Vesicle; accomplished suicide; acute stress; anticancer research; biological adaptation to stress; cell type; inorganic phosphate; neoplastic cell; neuronal cell body; novel; phosphatidylinositol 3-phosphate; phospholipid scramblase; prevent; rab GTP-Binding Proteins; receptor; tissue regeneration; trafficking

DESCRIPTION (provided by applicant): In animals, cells undergoing apoptosis and necrosis are rapidly internalized by other cells via phagocytosis (engulfment) and degraded inside phagocytes. The removal of these dying cells provides a safe means for eliminating unwanted and dangerous cells from the body and actively modulates immune responses. The study of apoptotic cell removal will shed light on inflammatory and auto-immune disorders, many of which are associated with an inefficient clearance of apoptotic cells from the human body. This study is also closely related to cancer research and treatment. My long-term objective is to understand the molecular mechanism that controls the recognition, engulfment, and degradation of apoptotic and necrotic cells. I use the nematode Caenorhabditis elegans, a small round worm as a model organism to identify genes and delineate pathways that control these evolutionarily conserved events and will apply the knowledge to understand similar processes in mammals, including humans. We have identified novel signaling events both upstream and downstream of C. elegans phagocytic receptor CED-1, which have provided conceptual advances in our understanding of how apoptotic cells are removed by engulfing cells. In the next project period we propose to broaden our research scope by investigating the mechanisms behind these events. We have identified phosphatidylserine (PS) as one of the "eat me" signals exposed on the surface of apoptotic cells and activate CED-1. We will further study the molecular mechanisms for the exposure and recognition of PS and other potential "eat me" signals in both apoptotic and engulfing cells (Aim 1). We will expand our study to the recognition and phagocytosis of necrotic touch neurons, which die in a caspase-independent manner and may employ unique mechanisms to attract engulfing cells (Aim 1). We have discovered that phagocytic receptor CED-1 not only initiates the engulfment, but also promotes the degradation of apoptotic cells through the recruitment and activation of downstream mediator DYN-1, the C. elegans ortholog of mammalian large GTPase dynamin. We will study the mechanism leading to the transient enrichment of DYN-1 to the surface of extending pseudopodia and phagosomes, which is important for its functions in both engulfment and phagosome maturation. One particular hypothesis to test is that the CED-1 pathway recruits DYN-1 via the collaborative efforts of CED-6 and phosphatidylinositol 4,5- phosphate (PI(4,5)P2) (Aim 2). We have established C. elegans as a unique model system for studying the degradation of apoptotic cells inside phagosomes, a process not well studied, and have identified the specific functions of two Rab GTPases, a PI3 kinase and its product phosphatidylinositol 3-phosphate (PI(3)P) in phagosome maturation. To reveal the mechanism of PI(3)P function and the relationship between PI(3)P and Rab GTPases, we will identify downstream effectors of PI(3)P and the events that they regulate (Aim 3). PUBLIC HEALTH RELEVANCE: This project studies how unwanted cells (cells that commit suicide or die due to injuries) are recognized, internalized, and digested by their engulfing cells, a process that protects human bodies from their harmful effects. Understanding the mechanisms controlling this process will have important therapeutic implications, since many inflammatory and auto-immune diseases are closely related to defects in removing dying cells from human bodies, and will further help develop new strategies to specifically eliminate tumor cells. This project will be conducted in a small round worm the nematode C. elegans, which uses evolutionarily conserved mechanisms to control cell death, and provides a powerful means to reveal the principle for biological actions in a relatively simple system.

描述（申请人提供）：在动物中，经历凋亡和坏死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。去除这些垂死的细胞提供了一种安全的方法，可以消除体内不需要的和危险的细胞，并积极调节免疫反应。凋亡细胞清除的研究将揭示炎症和自身免疫性疾病，其中许多疾病与人体内凋亡细胞清除效率低下有关。这项研究也与癌症研究和治疗密切相关。我的长期目标是了解控制凋亡和坏死细胞的识别、吞噬和降解的分子机制。我使用线虫秀丽隐杆线虫（一种小圆虫）作为模式生物来识别基因并描绘控制这些进化保守事件的途径，并将应用这些知识来理解哺乳动物（包括人类）的类似过程。我们已经确定了线虫吞噬受体 CED-1 上游和下游的新信号传导事件，这为我们理解吞噬细胞如何清除凋亡细胞提供了概念上的进展。在下一个项目期间，我们建议通过调查这些事件背后的机制来扩大我们的研究范围。我们已经确定磷脂酰丝氨酸（PS）是暴露在凋亡细胞表面并激活CED-1的“吃我”信号之一。我们将进一步研究凋亡细胞和吞噬细胞中 PS 和其他潜在“吃我”信号的暴露和识别的分子机制（目标 1）。我们将把我们的研究扩展到坏死的触觉神经元的识别和吞噬作用，这些神经元以不依赖半胱天冬酶的方式死亡，并且可能采用独特的机制来吸引吞噬细胞（目标 1）。我们发现吞噬细胞受体CED-1不仅启动吞噬，而且还通过招募和激活下游介质DYN-1（哺乳动物大GTP酶动力的线虫直系同源物）促进凋亡细胞的降解。我们将研究导致 DYN-1 瞬时富集到延伸伪足和吞噬体表面的机制，这对于其吞噬和吞噬体成熟的功能都很重要。需要测试的一个特定假设是，CED-1 途径通过 CED-6 和磷脂酰肌醇 4,5-磷酸 (PI(4,5)P2) 的协作来招募 DYN-1（目标 2）。我们建立了秀丽隐杆线虫作为研究吞噬体内凋亡细胞降解的独特模型系统，这一过程尚未得到充分研究，并确定了两种 Rab GTPases、一种 PI3 激酶及其产物磷脂酰肌醇 3-磷酸 (PI(3)P) 在吞噬体成熟中的特定功能。为了揭示 PI(3)P 功能的机制以及 PI(3)P 和 Rab GTPases 之间的关系，我们将确定 PI(3)P 的下游效应子及其调节的事件（目标 3）。公共健康相关性：该项目研究不需要的细胞（自杀或因受伤而死亡的细胞）如何被其吞噬细胞识别、内化和消化，这一过程可以保护人体免受其有害影响。了解控制这一过程的机制将具有重要的治疗意义，因为许多炎症和自身免疫性疾病与从人体中清除垂死细胞的缺陷密切相关，并将进一步有助于开发特异性消除肿瘤细胞的新策略。该项目将在一种小圆虫——秀丽隐杆线虫中进行，该线虫利用进化上保守的机制来控制细胞死亡，并提供了一种强有力的手段来揭示相对简单系统中生物作用的原理。