In Vivo Genetic Analysis of Compartmentalized Cell Elimination

区室化细胞消除的体内遗传分析

基本信息

批准号：
10456274
负责人：
Piya Ghose
金额：
$ 37.53万
依托单位：
UNIVERSITY OF TEXAS ARLINGTON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2026-05-31
项目状态：
未结题

项目摘要

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.

项目概要/摘要程序性细胞死亡（PCD）在机体健康中发挥着至关重要的作用，对于正常发育至关重要。细胞凋亡是基因编程的，调节基因的突变对癌症治疗有很大贡献反抗。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复杂的结构形态学。这对细胞死亡和清除的执行提出了挑战，因为亚细胞同一细胞不同区室的结构和微环境可能有很大差异。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，细胞延伸是专门的拆除后，电池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性，从而保证大脑的正常功能。这里要解决的核心问题是形态学上如何复杂的细胞被消除。线虫尾刺细胞是研究复杂细胞的有价值的模型退化，通过一种复杂的、可能普遍的、特定于区室的细胞死亡程序而死亡胚胎发育。我们将这个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，表明这可能是一种普遍的死亡程序。这尾刺细胞在区室杀伤和清除水平上也显示出差异的遗传调控。因此，对这种单细胞的研究可以为细胞消除的许多方面提供见解。这个提议利用尾刺细胞可以在活体动物以及动物体内的天然环境中进行研究的事实线虫的简单遗传学可以解决三个广泛相关的首要问题：线粒体如何贩运影响细胞过程的消除？哪些新基因控制 CCE 以及细胞死亡和清除广义上？哪些新基因调节其他复杂细胞（例如神经元）中的 CCE？我们将进行先进的细胞生物学和遗传学研究可以解决这些问题。所提出的实验，通过阐明基础细胞生物学的基本原理，将以多种方式推进细胞死亡领域的发展。他们会确定 PCD 和清除的新监管者；他们有潜力帮助设计针对这些疾病的靶向疗法细胞死亡相关疾病，包括癌症、神经变性、免疫和发育障碍。