Novel Killing and Clearance Programs in a Morphologically Complex Cell

项目摘要/摘要 程序性细胞死亡(PCD)在生物体健康中起着至关重要的作用，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一个标志。细胞凋亡是由基因决定的 调控基因的程序化和突变极大地导致了癌症治疗的耐药性。及时 清除细胞死亡后的细胞碎片也是至关重要的，因为缺陷会导致炎症，并与 自身免疫性疾病。体内的大多数细胞都是高度分化的，具有复杂的形态。这 在执行细胞死亡和清除方面提出了挑战，因为亚细胞结构和 同一细胞不同区域的微环境可能有很大不同。复杂的细胞可以作为一个整体死亡或在 一部份。在特定区域变性的情况下，细胞延伸，如轴突，被完全拆除 使细胞的其余部分完好无损。对于神经元来说，这样的修剪对于建立适当的 连通性，从而有助于正常的大脑功能。而不同的程序被认为是控制退化的 不同的细胞区域，精确的细胞生物学和分子机制控制隔室特异性 破坏还没有得到很好的理解。细胞每个部分的退化机制是相互关联的还是相互关联的？ 它们会相互影响吗？作为细胞凋亡的重要执行者，caspase在不同的细胞中扮演什么角色？ 车厢？结构不同的细胞室的清除在机械上是相似的和中介的吗？ 被相同的规范吞没计划？这项建议采用了线虫的遗传方法来解决 这些问题出现在尾尖细胞中，这是一种形态复杂的细胞，在发育过程中经历PCD。 初步数据表明，尾棘细胞是复杂细胞退化的信息模型， 鉴于其特定的间隔室退化动力学和在两者水平上的差异遗传调控 杀戮和清场。该项目的目标1描述了CED的新的、特定于隔室的功能- 3/caspase。AIM 2研究了细胞融合受体EFF-1如何介导一种新的过程特异性清除 程序。拟议的实验在几个方面推动了这一领域的发展。他们展示了一种新的模式 复杂细胞中的退化；它们识别程序性细胞死亡和清除的新调节器；它们 拥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 我们对轴突变性和修剪的理解，这在发育、可塑性、损伤中都很普遍 神经系统疾病。

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.