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

基本信息

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
项目类别：
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

项目摘要

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.

细胞中激活凋亡半胱天冬酶的生/死决策的机制超过一半的癌症患者接受电离辐射（IR）治疗。红外线疗法的成功取决于在细胞中造成足够的 DNA 损伤，迫使它们完成程序性细胞死亡的过程，已知作为细胞凋亡。不幸的是，一些细胞可以在辐射下存活并再生肿瘤，从而导致治疗失败（放射抗性）。由于放射疗法是三种最常用的治疗方法之一针对癌症，了解细胞在暴露于辐射后如何存活对于放射治疗至关重要优化。当细胞受到红外线损伤时，细胞内会触发死亡信号，从而激活凋亡半胱天冬酶。凋亡半胱天冬酶曾经被认为是细胞凋亡的标志。然而，现在是已知某些细胞可能会激活凋亡半胱天冬酶，但在暴露于辐射后不会死亡。细胞如何激活凋亡半胱天冬酶后存活仍然是一个活跃的研究领域。因此，本提案的目标目的是阐明细胞如何在辐射暴露后在半胱天冬酶活性中存活。我用的是果蝇，通常称为果蝇，用于研究细胞如何在半胱天冬酶活性中生存。细胞死亡，包括半胱天冬酶，以及果蝇的再生与脊椎动物具有相同的遗传和分子特征，因此，我们从中学到了什么模型生物很可能可以转化为人类。在目标 1 中，我将确定以下机制/基因：是细胞中激活凋亡半胱天冬酶的生/死决定的基础。具体来说，我将确定参与调节经历凋亡 caspase 活性但不影响细胞凋亡的信号通路不死。我决定针对已知对果蝇细胞存活至关重要的不同信号通路和人类，例如 Wnt（果蝇无翅）和 Notch 信号通路。我预计这项工作将揭示有助于细胞生/死决定的基因，这将为理解如何进行生/死决定提供基础癌细胞在暴露于红外线后仍能存活。在目标 2 中，我将研究细胞的后果在半胱天冬酶活性下存活但不会死亡。我有兴趣了解这些细胞的 DNA 有多稳定暴露于红外线后幸存下来以及半胱天冬酶在 DNA 修复中的作用。这些研究将为我们带来新的见解凋亡半胱天冬酶的新/新颖的非致命作用可用于改善放射治疗。总的来说，这项工作将提供对半胱天冬酶在帮助细胞存活后的作用的全面了解。暴露于辐射，它还将确定可以调节以改善治疗的机制人类癌症的结果。