Mechanisms that underlie the life/death decisions in a cell that activated apoptotic caspases

细胞中激活凋亡半胱天冬酶的生/死决策的机制

• 批准号: 10607815
• 负责人: Sarah Ivette Colon Plaza
• 金额: $ 4.04万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10607815
• 关键词: Adult; Apoptosis; Apoptotic; Area; Aspartic Acid; Biosensor; Cancer Patient; Caspase; Cell Death; Cell Survival; Cells; Cessation of life; Clinical; DNA; DNA Damage; DNA Maintenance; DNA Repair; DNA Repair Gene; Data; Development; Drosophila genus; Drosophila melanogaster; Dyes; Enzymes; Exposure to; Foundations; Genes; Genetic; Genome Stability; Goals; Human; Induction of Apoptosis; Ionizing radiation; Lead; Learning; Life; Loss of Heterozygosity; Malignant Neoplasms; Molecular; Natural regeneration; Nonhomologous DNA End Joining; Notch Signaling Pathway; Pathway interactions; Pattern; Peptide Hydrolases; Process; Proteins; Publishing; Radiation; Radiation exposure; Radiation therapy; Regulation; Research; Roentgen Rays; Role; Signal Pathway; Signal Transduction; Spatial Distribution; Structure; Testing; Tissues; Treatment Failure; Treatment outcome; Vertebrates; Wing; Work; cancer cell; common treatment; experience; experimental study; fly; gene product; genetic inhibitor; genome integrity; homologous recombination; improved; inhibitor; insight; interest; irradiation; model organism; notch protein; novel; pharmacologic; promoter; radiation resistance; recombinational repair; repaired; success; treatment optimization; tumor; tumorigenesis

Mechanisms that underlie the life/death decisions in a cell that activated apoptotic caspases More than half of cancer patients undergo ionizing radiation (IR) treatment. IR-therapy success relies on causing enough DNA damage in cells to force them to complete the process of programmed-cell death, known as apoptosis. Unfortunately, some cells can survive exposure to radiation and regenerate tumors, leading to treatment failure (radioresistance). Since radiotherapy is one of the three most common treatments used against cancer, understanding how cells survive after exposure to radiation is crucial for radiotherapy optimization. When a cell gets damaged by IR, a death signal is triggered in the cell leading to the activation of apoptotic caspases. Apoptotic caspases were once thought to be hallmarks of apoptosis. However, it is now known that some cells may activate apoptotic caspases but do not die after exposure to radiation. How cells survive after activating apoptotic caspases remains an active area of research. Thus, the goal of this proposal is to elucidate how cells survive caspase activity after radiation exposure. I use Drosophila melanogaster, commonly known as fruit fly, to study how cells survive caspase activity. Cell death, including caspases, and regeneration in Drosophila share genetic and molecular features with vertebrates, thus, what we learn from this model organism will likely be translatable to humans. In Aim 1, I will determine the mechanisms/genes that underlie the life/death decisions in a cell that activated apoptotic caspases. Specifically, I will identify the signaling pathways that are involved in the regulation of cells that experience apoptotic caspase activity but do not die. I have decided to target different signaling pathways that are known to be critical for cell survival in flies and humans, such as Wnt (wingless in flies) and Notch signaling pathways. I anticipate this work will reveal the genes that contribute to life/death decision of the cell, which will provide a foundation for understanding how cancer cells survive after exposure to IR. In Aim 2, I will investigate the consequences of having cells that survive caspase activity but do not die. I am interested in understanding how stable the DNA of these cells is after surviving exposure to IR and the role of caspases in DNA repair. These studies will bring new insights to new/novel non-lethal roles of apoptotic caspases that could be exploited to improve radiotherapy. Collectively, this work will provide a comprehensive understanding of the role of caspases in aiding cells survive after exposure to radiation and it also will identify mechanisms that may be modulated to improve treatment outcome in human cancers.

基于激活凋亡胱天蛋白酶细胞中生死决策的机制 超过一半的癌症患者接受电离辐射（IR）治疗。 IR-Therapy成功依赖于 导致细胞中足够的DNA损伤迫使它们完成编程细胞死亡的过程，已知 作为凋亡。不幸的是，某些细胞可以在暴露于辐射和再生肿瘤中生存，导致 治疗失败（放射线）。由于放射疗法是三种最常见的治疗方法之一 针对癌症，了解暴露于辐射后的细胞如何生存对于放射疗法至关重要 优化。当细胞因IR损坏时，在细胞中触发死亡信号，导致激活 凋亡的胱天蛋白酶。凋亡的胱天蛋白酶曾经被认为是凋亡的标志。但是，现在是 知道某些细胞可能会激活凋亡的胱天蛋白酶，但在暴露于辐射后不会死亡。细胞如何 激活凋亡的胱天蛋白酶后生存仍然是一个活跃的研究领域。因此，该提议的目标 是为了阐明辐射暴露后的细胞如何生存caspase活性。我使用果蝇Melanogaster， 通常称为果蝇，以研究细胞如何生存caspase活性。细胞死亡，包括胱天蛋白酶，以及 果蝇的再生与脊椎动物共享遗传和分子特征，因此，我们从中学到了什么 模型有机体可能可以翻译成人类。在AIM 1中，我将确定机制/基因 基于激活凋亡胱天蛋白酶的细胞中的生死决策。具体来说，我将确定 与经历凋亡caspase活性的细胞调节有关的信号通路，但要做 不死。我已决定靶向不同的信号通路，这些信号通路对于果蝇中的细胞存活至关重要 和人类，例如wnt（无翅膀）和缺口信号通路。我预计这项工作将揭示 有助于细胞生死决策的基因，这将为理解如何理解如何 暴露于IR后，癌细胞生存。在AIM 2中，我将调查拥有细胞的后果 在胱天蛋白酶活动中生存，但不会死亡。我有兴趣了解这些细胞的DNA的稳定性 在暴露于IR和胱天蛋白酶在DNA修复中的作用后。这些研究将带来新的见解 凋亡胱天蛋白酶的新型/新型非致命作用，可以利用以改善放射疗法。共同 这项工作将对胱天蛋白酶在辅助细胞中的作用进行全面了解 暴露于辐射，它还将确定可能调节以改善治疗的机制 人类癌症的结果。