To ensure tissue homeostasis in multicellular organisms, cells damaged by environmental insults (such as UV irradiation) have to be either repaired or eliminated. Misregulation of the decision between cell repair and cell death plays an important role in degenerative diseases of the retina, such as age-related macular degeneration, as well as more generally in cancer. Insight into the regulation of cellular damage defense and cell death will increase our ability to prevent and/or treat such diseases. Current models suggest that the balance between cell survival signals and pro-apoptotic stimuli controls the decision between repair and death of a cell. How these competing signals are integrated and interpreted to achieve accurate control over cell fate in vivo is incompletely understood. Studies using genetically accessible model systems are required to gain further insight into this regulatory system. The applicant has performed preliminary studies to analyze the regulation of cellular life-death decisions in the retina. These studies show that the Forkhead Box O transcription factor Foxo as well as the AP-1 transcription factor DFos are required downstream of the Jun-N-terminal Kinase signaling pathway for the apoptotic response to UV-induced DNA damage in the developing Drosophila retina. Importantly, these studies show that UV-induced apoptosis is repressed by survival signals emanating from Receptor Tyrosine Kinase pathways, which are known to inactivate Foxo. These data suggest that integrating stress and survival signals through Foxo drives the decision between cell death and repair of damaged cells in vivo. This model will be tested by addressing the following specific aims experimentally: (i) Analyze the regulation of UV-induced transcriptional responses in the retina. Using expression profiling approaches, the regulation of pro-apoptotic and pro-survival gene expression programs will be analyzed in the retina. (ii) Test whether biphasic activation of JNK signaling governs the cellular response to UV. The applicant proposes that JNK activation in response to UV stress occurs in two phases: an initial phase that promotes cell recovery and, when DNA damage persists, a second phase that induces pro-apoptotic gene expression. Genetic experimentation will be used to test this model. (iii) Identify regulators of the retinal UV response using genetic approaches. One advantage of the Drosophila system is the ability to use genetic screens to rapidly identify new components of signaling pathways. Here, such approaches will be used to identify new genes that will allow addressing specific questions regarding the control of cell fate and signaling specificity. The experiments proposed here are expected to significantly advance our understanding of the regulation of cellular life/death decisions in intact tissues and will therefore be of relevance to future rational therapeutic approaches for degenerative diseases.
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