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

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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.