In Vivo Genetic Analysis of Compartmentalized Cell Elimination

项目概要/摘要 程序性细胞死亡（PCD）在生物体健康中起重要作用，对正常发育至关重要。 细胞凋亡是基因编程的，调控基因的突变对癌症治疗有很大贡献 阻力细胞死亡后及时清除细胞碎片也至关重要，因为缺陷会导致炎症 与自身免疫性疾病有关身体中的大多数细胞都是高度分化的， 形态学这在细胞死亡和清除的执行中提出了挑战，因为亚细胞死亡和清除是一个非常复杂的过程。 同一细胞的不同区室的结构和微环境可能差异很大。复杂细胞 可以整体或部分死亡。在区域特异性变性的情况下，细胞延伸仅限于 剩下的部分都被拆除了。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。这里讨论的中心问题是形态学上如何 复杂细胞被消除。梭elegans尾棘细胞是研究复杂细胞有价值的模型 退化，通过一个精心制作的，可能是普遍的，特定于细胞死亡的程序死亡， 胚胎发育。我们将这一非凡的计划称为区室化细胞消除（CCE）， 这也发生在一组性别特异性神经元中，表明这可能是一个普遍的死亡程序。的 尾棘细胞还在隔室杀伤和清除水平上显示出差异遗传调节。 因此，对这种单细胞的研究可以提供对细胞消除的许多方面的见解。这项建议 利用了这样一个事实，即尾棘细胞可以在活体动物的自然环境中进行研究， C. elegans来解决三个广泛相关的首要问题：线粒体如何 贩卖影响细胞过程消除？什么样的新基因控制着CCE，从而导致细胞死亡和清除 广泛？在其他复杂细胞（如神经元）中，有哪些新基因调控CCE？我们将执行高级 细胞生物学和遗传学研究来解决这些问题。实验通过照明， 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。他们将 确定PCD和清除的新调节剂;它们有可能帮助设计针对 细胞死亡相关疾病，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.