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.

项目摘要/摘要 程序性细胞死亡（PCD）在有机体健康中具有至关重要的作用，是正常的重要组成部分 发展。不适当的细胞存活是肿瘤进展的标志。细胞凋亡在遗传上 调节基因的程序和突变极大地促进了癌症耐药性。及时 细胞死亡后细胞碎屑的清除也至关重要，因为缺陷会导致炎症，并与 自身免疫性疾病。体内的大多数细胞高度分化，并具有复杂的形态。这 在细胞死亡和清除执行中提出挑战，作为亚细胞体系结构和 同一细胞不同区域的微环境可能有很大差异。复杂的细胞可以整体或整个死亡 部分。在区域特异性变性的情况下，细胞延伸（例如轴突）仅被拆除 使其余的细胞完整。对于神经元，这种修剪对于建立适当的修剪很重要 连通性，因此为了适当的大脑功能。虽然认为不同的程序可以控制退化 在不同的细胞区域，有关隔室特异性的精确细胞生物学和分子机制 破坏还没有很好地理解。是细胞相互关联或DO的每个部分中的退化机制 他们互相影响吗？胱天蛋白酶的作用，凋亡的基本执行者在不同的细胞中扮演 车厢？是结构上各种细胞室的清除在机械上相似和介导的清除 通过同样的规范吞噬计划？该提议采用秀丽隐杆线虫中的遗传方法来解决 这些问题在尾尖细胞中，这是一种在发育过程中经历PCD的形态复杂细胞。 初步数据表明，尾尖单元是复杂细胞变性的信息模型， 鉴于其隔室特异性变性动力学和两者水平的差异遗传调节 杀人和清理。该项目的AIM 1是CED-的新颖，隔室特异性功能的特征。 3/caspase。 AIM 2检查细胞融合受体EFF-1如何介导新的过程特异性清除率 程序。提出的实验以多种方式推进了该领域。他们展示了一种新的模式 复杂细胞的变性；他们确定了程序性细胞死亡和清除的新型调节因子；他们 具有帮助设计针对细胞死亡相关疾病的有针对性疗法的潜力；他们可能会拓宽 我们对神经突变性和修剪的理解，在发育，可塑性，损伤中很普遍 和神经系统的疾病。