In Vivo Genetic Analysis of Compartmentalized Cell Elimination

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，对正常发育至关重要。 细胞凋亡是由基因决定的，调控基因的突变对癌症治疗有很大贡献。 抵抗。细胞死亡后及时清除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有关。体内的大多数细胞都高度分化，并具有错综复杂的 形态特征。这给执行细胞死亡和清除带来了挑战，因为亚细胞 同一细胞的不同隔间的结构和微环境可能会有很大的不同。复杂细胞 可以作为一个整体或部分死亡。在特定区域退化的情况下，细胞延伸是唯一的 被拆除了，牢房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。这里讨论的中心问题是如何在形态上 复杂的细胞被消除了。线虫尾棘细胞是研究复杂细胞的有价值的模型 退化，通过精心设计的、可能是普遍的、特定于间隔室的细胞死亡程序在 胚胎发育。我们将这一非凡的计划命名为分区细胞消除(CCE)， 这也发生在一组特定性别的神经元中，这表明这可能是一种普遍的死亡程序。这个 尾棘细胞在隔室杀伤和清除水平上也表现出不同的遗传调控。 因此，对这种单个细胞的研究可以为细胞消除的许多方面提供见解。这项建议 利用这一事实，尾尖细胞可以在活动物的天然环境中进行研究，以及 线虫的简便遗传学解决了三个广泛相关的首要问题：线粒体是如何 贩运会影响细胞过程的消除吗？什么新基因控制着CCE，从而导致细胞死亡和移除 宽泛地说？在其他复杂的细胞，如神经元中，哪些新的基因调节CCE？我们将表演先进的 细胞生物学和遗传学研究来解决这些问题。建议的实验，通过照亮 基本细胞生物学的基本原理，将在几个方面推进细胞死亡领域。他们会 确定PCD和清除的新调节器；它们有可能帮助设计针对 与细胞死亡相关的疾病，包括癌症、神经变性、免疫和发育障碍。

Project Summary/Abstract Programmed cell death (PCD) and has vital roles in organismal health and is essential to normal development. 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 compartments 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 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. The central question addressed here is how morphologically complex cells are eliminated. The C. elegans tail-spike cell is a valuable model to study complex cell degeneration, dying through an elaborate, likely universal, compartment-specific program of cell death during embryonic development. We have termed this remarkable program Compartmentalized Cell Elimination (CCE), which also occurs in a set of sex-specific neurons, suggesting this may be a universal program of death. The tail-spike cell also shows differential genetic regulation at the levels of both compartmental killing and clearance. As such, a study of this single cell can provide insights on many facets of cell elimination. This proposal leverages the fact that the tail-spike cell can be studied in its native context in the living animal as well as the facile genetics of C. elegans to tackle three broadly related overarching questions: How does mitochondrial trafficking influence cell process elimination? What novel genes govern CCE and hence cell death and removal broadly? What novel genes regulate CCE in other complex cells, such as neurons? We will perform advanced cell biological and genetic studies to address these questions. The proposed experiments, by illuminating fundamental principles of basic cell biology, will advance the field of cell death in several ways. They will identify novel regulators of PCD and clearance; they hold the potential to help devise targeted therapies against cell-death-related disease, including cancer, neurodegeneration, immune and developmental disorders.