Phagocytic Removal of Apoptotic and Necrotic Cells

吞噬去除凋亡和坏死细胞

• 批准号: 7993913
• 负责人: Zheng Zhou
• 金额: $ 8.85万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-12 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7993913
• 关键词: 1-Phosphatidylinositol 3-Kinase; ATP-Binding Cassette Transporters; Adult; Animal Model; Animals; Apoptosis; Apoptotic; Award; Belief; Biological; Biological Models; Caenorhabditis elegans; Caspase; Cell Communication; Cell Death; Cells; 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; Mammals; Mediator of activation protein; Molecular; Monomeric GTP-Binding Proteins; Necrosis; Nematoda; Neurodegenerative Disorders; Neurons; Orthologous Gene; PH Domain; Pathway interactions; Phagocytes; Phagocytosis; Phagosomes; Phosphatidylinositols; Phosphatidylserines; Play; Process; Production; Proteins; Pseudopodia; 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; public health relevance; 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，经历细胞凋亡和坏死的细胞通过吞噬作用(吞噬)被其他细胞迅速内化，并在吞噬细胞内降解。清除这些濒临死亡的细胞提供了一种安全的方法，可以清除体内不需要的和危险的细胞，并积极调节免疫反应。对凋亡细胞清除的研究将有助于揭示炎症和自身免疫障碍，其中许多疾病与人体对凋亡细胞的清除效率低下有关。这项研究也与癌症的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识别、吞噬和降解的分子机制。我使用线虫线虫，一种小的圆形蠕虫作为模式生物，来识别控制这些进化保守事件的基因和途径，并将这些知识应用于理解哺乳动物的类似过程，包括人类。我们已经在线虫吞噬细胞受体CED-1的上游和下游发现了新的信号事件，这些信号事件为我们理解如何通过吞噬细胞去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的“吃我”信号之一，并激活CED-1。我们将进一步研究在凋亡和吞噬细胞中暴露和识别PS和其他潜在的“Eat Me”信号的分子机制(目标1)。我们将把我们的研究扩展到坏死性触摸神经元的识别和吞噬作用，这些神经元以caspase非依赖的方式死亡，并可能使用独特的机制来吸引吞噬细胞(目标1)。我们已经发现，吞噬细胞受体CED-1不仅启动吞噬，而且通过募集和激活下游介体Dyn-1促进凋亡细胞的降解。Dyn-1是线虫大GTP酶Dynamin的同源基因。我们将研究导致Dyn-1在扩张的伪足和吞噬小体表面短暂聚集的机制，这对其在吞噬和吞噬小体成熟中的作用都是重要的。一个需要检验的特殊假设是，CED-1途径通过CED-6和磷脂酰肌醇4，5-磷酸(PI(4，5)P2)的协同作用招募Dyn-1(目标2)。我们已经建立了线虫作为一个独特的模型系统来研究吞噬体内凋亡细胞的降解过程，这一过程还没有得到很好的研究，并鉴定了两个Rab GTP酶，一个PI3激酶及其产物磷脂酰肌醇3-磷酸(PI(3)P)在吞噬体内成熟过程中的特殊功能。为了揭示PI(3)P的作用机制以及PI(3)P与Rab GTP酶之间的关系，我们将识别PI(3)P的下游效应因子及其调控的事件(目标3)。与公共卫生相关：该项目研究不需要的细胞(自杀或因伤害死亡的细胞)如何被其吞噬的细胞识别、内化和消化，这是一个保护人体免受其有害影响的过程。了解控制这一过程的机制将具有重要的治疗意义，因为许多炎症性和自身免疫性疾病与从人体中清除濒临死亡的细胞的缺陷密切相关，并将进一步有助于开发专门清除肿瘤细胞的新策略。这个项目将在一种小的圆形蠕虫线虫中进行，这种线虫使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的系统中的生物作用原理。