Elucidating the role of the Integrated Stress Response pathway in tissue homeostasis

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PROJECT ABSTRACT Elucidating the role of the Integrated Stress Response pathway in tissue homeostasis Metazoa have evolved stress response pathways to combat internal and external stressors (e.g., nutrient deprivation, changes in environmental conditions, toxic insults). The Integrated Stress Response (ISR) is one such evolutionarily conserved pathway that mediates adaptation to cellular stress. Since its discovery in yeast, much effort has been dedicated to studying the role of ISR signaling in mediating the cellular response to exogenous stress. In higher organisms, many specialized cell types have evolved to rely on the ISR to maintain homeostasis: notable examples of this include metabolically active cells such as hepatocytes and adipocytes, highly secretory cells such as b-islet cells of the pancreas, and neurons with high protein turnover such as photoreceptors. Our current understanding of ISR signaling in maintaining tissue homeostasis largely comes from phenotypic observations in loss-of-function mutants, yet little is known about the underlying molecular and cell biology of such regulation. This proposal seeks to gain new insights into the precise molecular and cell biological mechanisms governed by ISR signaling in maintaining tissue homeostasis. We will use the Drosophila fat tissue and ovary as a discovery platform, owing to the breadth of genetic and molecular biology tools available for manipulation of these tissues. The different branches of ISR signaling culminate in the highly conserved transcription factor, ATF4. We recently described a role for Drosophila ATF4 in the regulation of oogenesis. Our preliminary data revealed that while some of the oogenesis defects (e.g., oocyte maturation) arise from autonomous requirement for Atf4 in the ovary, several others (e.g., yolk protein accumulation, egg laying) are mediated tissue non-autonomously by Atf4 in the fat tissues surrounding the ovary. Based on these data, we test a role for ISR signaling as a fat tissue metabolic sensor, which informs peripheral tissue function non-autonomously. Leveraging our extensive background in molecular and cell biology techniques with powerful Drosophila genetic tools, we will pursue three projects to establish the role for ISR signaling 1) in regulating steroid hormone signaling in fat tissues, 2) in fat tissue-mediated neuromodulation, and 3) in the mRNA translational control in the ovary. Gaining molecular understanding of the role for the ISR in tissue homeostasis will fundamentally inform our approach to experimentally and therapeutically improve tissue function. The advancements from this study will also bear vast pathobiological relevance since ISR dysregulation is associated with an ever-increasing number of diseases, from diabetes to neurodegeneration and cancer.