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: 9191604
• 负责人: Piya Ghose
• 金额: $ 5.8万
• 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/9191604
• 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 Death; 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; Inflammation; Injury; Interphase Cell; Kinetics; Label; Lead; Left; Light; Link; Mediating; Membrane; Membrane Fusion; Methods; Microscopy; Mitochondria; Modeling; Molecular; Morphology; Mutation; Nematoda; Nervous System Physiology; Neurites; Neurons; Pathology; Peptide Hydrolases; Play; Process; Proteins; Public Health; Regulation; Regulator Genes; Reporter; Resistance; Resolution; Role; Site; Stereotyping; System; Tail; Tumor Suppressor Proteins; Vesicle; abstracting; cancer therapy; functional loss; gene discovery; genetic approach; human disease; insight; killings; mutant; nervous system disorder; neuron loss; neuronal cell body; novel; programs; receptor; relating to nervous system; research study; 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.

项目总结/摘要 程序性细胞死亡（PCD）在生物体健康中起着重要作用，是正常发育的重要组成部分。 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 调节基因中的程序化和突变极大地促进了癌症治疗抗性。及时 细胞死亡后细胞碎片的清除也是至关重要的，因为缺陷会导致炎症，并与 自身免疫性疾病身体中的大多数细胞是高度分化的，并且具有复杂的形态。这 在细胞死亡和清除的执行方面提出了挑战，因为亚细胞结构和 同一细胞的不同区域的微环境可能差异很大。复杂的细胞可以作为一个整体死亡， 部分在区域特异性变性的情况下，细胞延伸，如轴突，被专门拆除 而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，从而保持正常的大脑功能。虽然不同的程序被认为是控制退化 不同的细胞区域，精确的细胞生物学和分子机制，管理隔室特异性 破坏并不被很好地理解。细胞各部分的退化机制是相互关联的还是 它们会互相影响吗凋亡的主要执行者半胱天冬酶在不同的细胞中起着什么样的作用 隔间？结构不同的细胞区室的清除机制是否相似， 被同样的规范吞噬程序所吞噬该提案采用了C中的遗传方法。elegans地址 这些问题在尾棘细胞，一个形态复杂的细胞，在发展过程中经历PCD。 初步数据表明，尾棘细胞是复杂细胞变性的信息模型， 考虑到其在两个水平上的隔室特异性退化动力学和差异遗传调节， 杀戮和清理该项目的目标1描述了CED的新的、特定于隔室的功能， 3/caspase。目的2研究细胞融合受体EFF-1如何介导新的过程特异性清除 程序.拟议中的实验在几个方面推动了该领域的发展。他们展示了一种新的 在复杂的细胞退化;他们确定新的调节程序性细胞死亡和清除;他们 具有帮助设计针对细胞死亡相关疾病的靶向疗法的潜力;它们可能会扩大 我们对神经突变性和修剪的理解，这在发育，可塑性，损伤中普遍存在， 和神经系统疾病。