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

激活凋亡半胱天冬酶的细胞中决定生/死的机制 超过一半的癌症患者接受电离辐射（IR）治疗。IR治疗的成功依赖于 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， 细胞凋亡。不幸的是，一些细胞可以在暴露于辐射下存活并再生肿瘤，导致肿瘤细胞的增殖。 治疗失败（辐射抗性）。由于放射治疗是三种最常用的治疗方法之一， 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.当细胞被红外线损伤时，细胞中的死亡信号被触发，导致激活 凋亡半胱天冬酶。凋亡半胱天冬酶曾被认为是细胞凋亡的标志。但现在 已知一些细胞可以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 活化凋亡半胱天冬酶后的存活仍然是一个活跃的研究领域。因此，本提案的目的 是阐明细胞如何在辐射暴露后存活半胱天冬酶活性。我用果蝇， 通常被称为果蝇，研究细胞如何在半胱天冬酶活性下存活。细胞死亡，包括半胱天冬酶，和 果蝇的再生与脊椎动物有着共同的遗传和分子特征，因此，我们从中学到的是， 模式生物很有可能被移植到人类身上。在目标1中，我将确定 是激活凋亡半胱天冬酶的细胞中决定生死的基础。具体来说，我将确定 参与调节经历凋亡半胱天冬酶活性的细胞的信号传导途径， 而不是死我已经决定针对不同的信号通路，这些通路对果蝇细胞的存活至关重要 和人类，如Wnt（苍蝇无翅）和Notch信号通路。我预计这项工作将揭示 这些基因有助于细胞的生/死决定，这将为理解细胞如何 癌细胞在暴露于IR后存活。在目标2中，我将研究细胞 存活半胱天冬酶活性但不死亡。我对了解这些细胞的DNA有多稳定很感兴趣 在暴露于IR后存活以及半胱天冬酶在DNA修复中的作用。这些研究将带来新的见解， 凋亡半胱天冬酶的新的/新的非致命作用，可用于改善放射治疗。总的来说， 这项工作将提供一个全面的理解，在帮助细胞生存后，半胱天冬酶的作用。 它还将确定可能被调节以改善治疗的机制 人类癌症的结果。

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.