In Vivo Genetic Analysis of Compartmentalized Cell Elimination

区室化细胞消除的体内遗传分析

• 批准号: 10725086
• 负责人: Piya Ghose
• 金额: $ 6.53万
• 依托单位: UNIVERSITY OF TEXAS ARLINGTON
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10725086
• 关键词: Address; Animals; Apoptosis; Architecture; Autoimmune Diseases; Biological; Brain; Caenorhabditis elegans; Cell Death; Cell physiology; Cells; Cellular biology; Cessation of life; Complex; Defect; Development; Disease; Embryonic Development; Excision; Genes; Genetic; Genetic study; Health; Homeostasis; Immune System Diseases; Inflammation; Injury; Interphase Cell; Lead; Link; Malignant Neoplasms; Mitochondria; Modeling; Morphology; Mutation; Nerve Degeneration; Neurons; Public Health; Regulation; Regulator Genes; Resistance; Role; cancer therapy; developmental disease; experimental study; genetic analysis; in vivo; insight; novel; programs; sex; targeted treatment; trafficking; tumor

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.

项目摘要/摘要 程序性细胞死亡（PCD），在有机体健康中具有至关重要的作用，对于正常发育至关重要。 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。细胞死亡后细胞碎片的及时清除也至关重要，因为缺陷导致炎症 并与自身免疫性疾病有关。体内大多数细胞高度分化，并且复杂 形态。这在执行细胞死亡和清除方面提出了挑战，作为亚细胞 同一细胞的不同隔室的结构和微环境可能会大不相同。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，细胞扩展仅是 拆除使其余的细胞完好无损。对于神经元，这种修剪对于建立适当的修剪很重要 连通性，因此为了适当的大脑功能。这里解决的主要问题是形态学如何 消除复杂的细胞。秀丽隐杆线虫尾尖单元是研究复杂细胞的宝贵模型 堕落，通过精心制作的，可能是通用的隔室特定的细胞死亡程序 胚胎发展。我们已经称这一非凡的程序分隔了细胞消除（CCE）， 这也发生在一系列特定性别的神经元中，这表明这可能是一个普遍的死亡计划。这 尾尖细胞还显示了隔室杀戮和清除水平的差异遗传调节。 因此，对该单个细胞的研究可以为消除细胞的许多方面提供见解。这个建议 利用了一个事实，即可以在活动物中的本地环境以及 秀丽隐杆线虫的便利遗传学，以解决三个广泛相关的总体问题：线粒体如何 贩运影响细胞过程消除？哪些新型基因控制CCE，因此细胞死亡和去除 广泛？哪些新型基因调节其他复杂细胞（例如神经元）中的CCE？我们将执行高级 细胞生物学和遗传研究以解决这些问题。提出的实验，通过照明 基本细胞生物学的基本原理将以几种方式推进细胞死亡领域。他们会的 确定PCD和清除的新型调节剂；他们有潜力帮助设计有针对性的疗法 与细胞死亡有关的疾病，包括癌症，神经退行性，免疫和发育障碍。