Novel Killing and Clearance Programs in a Morphologically Complex Cell

形态复杂细胞中的新型杀伤和清除程序

• 批准号: 9326839
• 负责人: Piya Ghose
• 金额: $ 6.1万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-16 至 2019-08-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9326839
• 关键词: Address; Animals; Apoptosis; Apoptosis Regulation Gene; Apoptotic; Architecture; Autoimmune Diseases; Axon; BCL2 gene; Biological; Biological Neural Networks; Brain; CASP3 gene; Caenorhabditis elegans; Caspase; Cell Compartmentation; Cell Death; Cell Differentiation process; Cell Survival; Cell fusion; Cell membrane; Cell physiology; Cells; Cellular Morphology; Cessation of life; Complex; Data; Defect; Development; Disease; Distal; Event; Excision; F-Box Proteins; Functional disorder; Genes; Genetic; Genetic Transcription; Goals; Health; Human; Image; Immune System Diseases; Immune System and Related Disorders; Inflammation; Injury; Interphase Cell; Kinetics; Label; Lead; Light; Link; Mediating; Membrane; Membrane Fusion; Methods; Microscopy; Mitochondria; Modeling; Molecular; Morphology; Mutation; Nematoda; Nervous System Physiology; Neurites; Neurons; Pathology; Peptide Hydrolases; Phagocytes; Play; Process; Proteins; Public Health; Regulation; Regulator Genes; Reporter; Resistance; Resolution; Role; Site; Stereotyping; System; Time; Tumor Suppressor Proteins; Vesicle; cancer therapy; experimental study; functional loss; gene discovery; genetic approach; human disease; imaging study; information model; insight; killings; mutant; nervous system disorder; neuron loss; neuronal cell body; novel; programs; receptor; relating to nervous system; targeted treatment; trafficking; transcription factor; tumor; tumor progression

Project Summary/Abstract Programmed cell death (PCD) has vital roles in organismal health and is an essential part of normal development. Inappropriate cell survival is a hallmark of tumor progression. Apoptosis is genetically programmed and mutations in regulatory genes contribute greatly to cancer therapy resistance. Timely clearance of cellular debris following cell death is also critical as defects lead to inflammation and are linked to autoimmune disease. Most cells in the body are highly differentiated and have intricate morphologies. This presents challenges in the execution of cell death and clearance, as the subcellular architecture and microenvironment of different regions of the same cell may differ vastly. Complex cells can die as a whole or in part. In the case of region-specific degeneration, cellular extensions, such as axons, are exclusively dismantled leaving the rest of the cell intact. For neurons, such pruning is important in establishing appropriate connectivity and thus for proper brain function. While distinct programs are thought to control the degeneration of different cell regions, the precise cell biological and molecular mechanisms governing compartment-specific destruction are not well understood. Are degenerative mechanisms in each part of the cell inter-related or do they influence one another? What role do caspases, essential executers of apoptosis, play in the different cell compartments? Is the clearance of structurally diverse cell compartments mechanistically similar and mediated by the same canonical engulfment programs? This proposal takes a genetic approach in C. elegans to address these questions in the tail-spike cell, a morphologically complex cell that undergoes PCD during development. Preliminary data demonstrates that the tail-spike cell is an informative model for complex cell degeneration, given its compartment-specific degeneration kinetics and differential genetic regulation at the levels of both killing and clearance. Aim 1 of the project characterizes novel, compartment-specific, functions of CED- 3/caspase. Aim 2 examines how the cell fusion receptor EFF-1 mediates a novel process-specific clearance program. The proposed experiments advance the field in several ways. They demonstrate a new mode of degeneration in complex cells; they identify novel regulators of programmed cell death and clearance; they hold the potential to help devise targeted therapies against cell-death-related disease; and they may broaden our understanding of neurite degeneration and pruning, which are prevalent in development, plasticity, injury and disease of the nervous system.

项目概要/摘要 程序性细胞死亡（PCD）在机体健康中发挥着至关重要的作用，是正常生命活动的重要组成部分。 发展。不适当的细胞存活是肿瘤进展的标志。细胞凋亡是遗传性的 调控基因的编程和突变极大地导致了癌症治疗耐药性。及时 细胞死亡后细胞碎片的清除也至关重要，因为缺陷会导致炎症并与 自身免疫性疾病。体内的大多数细胞都高度分化并具有复杂的形态。这 由于亚细胞结构和 同一细胞不同区域的微环境可能存在很大差异。复杂的细胞可以整体死亡或部分死亡 部分。在区域特异性变性的情况下，细胞延伸，例如轴突，被专门拆除 保持细胞的其余部分完好无损。对于神经元来说，这种修剪对于建立适当的 连接性，从而保证大脑的正常功能。虽然不同的程序被认为可以控制退化 不同细胞区域的精确细胞生物学和分子机制控制区室特异性 破坏还没有被很好地理解。细胞各部分的退行性机制是否相互关联？ 他们互相影响吗？ Caspases是细胞凋亡的重要执行者，在不同细胞中发挥什么作用 隔间？结构不同的细胞区室的清除在机制上是否相似并且是介导的 通过相同的规范吞没计划？该提案采用秀丽隐杆线虫的遗传方法来解决 这些问题都存在于尾刺细胞中，尾刺细胞是一种形态复杂的细胞，在发育过程中会经历 PCD。 初步数据表明尾尖细胞是复杂细胞变性的信息模型， 考虑到其隔室特异性变性动力学和两个水平上的差异遗传调控 杀戮和清除。该项目的目标 1 描述了 CED-的新颖的、特定于隔间的功能 3/半胱天冬酶。目标 2 检查细胞融合受体 EFF-1 如何介导新的过程特异性清除 程序。所提出的实验在几个方面推动了该领域的发展。他们展示了一种新模式 复杂细胞的变性；他们发现了程序性细胞死亡和清除的新调节因子；他们 有潜力帮助设计针对细胞死亡相关疾病的靶向疗法；他们可能会扩大 我们对神经突变性和修剪的理解，它们在发育、可塑性、损伤中普遍存在 和神经系统疾病。