Phagocytic Removal of Apoptotic and Necrotic Cells

吞噬去除凋亡和坏死细胞

• 批准号: 7678609
• 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/7678609
• 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; 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（由申请方提供）：在动物中，经历凋亡和坏死的细胞通过吞噬作用（吞噬）被其他细胞迅速内化，并在吞噬细胞内降解。这些垂死细胞的去除提供了一种安全的手段，用于消除身体中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疾病，其中许多与人体凋亡细胞的清除效率低下有关。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，一个小的圆形蠕虫作为模式生物，以确定基因和描绘控制这些进化保守的事件的途径，并将应用知识来了解哺乳动物，包括人类的类似过程。我们已经确定了新的信号事件的上游和下游的C。elegans吞噬细胞受体CED-1，这为我们理解凋亡细胞如何被吞噬细胞清除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）作为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“吃我”信号的分子机制（目的1）。我们将把我们的研究扩展到坏死触觉神经元的识别和吞噬，这些神经元以不依赖半胱天冬酶的方式死亡，并可能采用独特的机制吸引吞噬细胞（目的1）。我们发现，吞噬受体CED-1不仅启动吞噬，而且通过募集和激活下游介质DYN-1，C.哺乳动物大GT3发动蛋白的直向同源物。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，这对于其在吞噬和吞噬体成熟中的功能都很重要。要检验的一个特定假设是CED-1途径通过CED-6和磷脂酰肌醇4，5-磷酸（PI（4，5）P2）的协同努力募集DYN-1（目的2）。我们已经建立了C. elegans作为一种独特的模型系统，用于研究吞噬体内凋亡细胞的降解，这一过程尚未得到很好的研究，并且已经鉴定了两种Rab GTP酶，一种PI 3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异性功能。为了揭示PI（3）P功能的机制以及PI（3）P和Rab GTP酶之间的关系，我们将鉴定PI（3）P的下游效应物以及它们调节的事件（目的3）。公共卫生关系：该项目研究不需要的细胞（自杀或因受伤而死亡的细胞）如何被吞噬细胞识别，内化和消化，这是一个保护人体免受有害影响的过程。了解控制这一过程的机制将具有重要的治疗意义，因为许多炎症和自身免疫疾病与从人体中去除垂死细胞的缺陷密切相关，并将进一步帮助开发专门消除肿瘤细胞的新策略。本项目将在一种小型圆线虫C. elegans，它使用进化上保守的机制来控制细胞死亡，并提供了一个强有力的手段来揭示在一个相对简单的系统中的生物行为的原则。