Regulation of cell growth and proliferation

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PROJECT SUMMARY This MIRA/R35 application was conceived to replace R01 grants GM126033 and GM124434. These projects address the regulation of cell growth and proliferation, a central topic in cell and developmental biology that is relevant to the many human disorders in which cell growth is dysregulated (e.g. degenerative diseases, inflammatory conditions, cancers). Our NIGMS-supported research reaches back to 1994, with the singular objective to understand how cell proliferation is regulated in vivo, in the complex context of the animal body. Our research addresses fundamental issues: how growth signaling drives cell growth, how cell growth-associated metabolism regulates cell cycle progression, and how environmental, cellular and molecular interactions regulate growth signaling activities in vivo. We primarily utilize genetic approaches in Drosophila, with a current focus on intestinal epithelial renewal, but we also seize opportunities to translate our findings using human cells and organoids. Two of our projects are testing the unorthodox hypothesis that growth-dependent translation of mRNAs encoding limiting cell cycle regulators determines whether, and how fast, cells proliferate. We have validated this mechanism in Drosophila and human cells, and are currently investigating how upstream EGFR/RAS/ERK and Insulin/PI3K/mTOR signaling interface with the growth-dependent translation of factors that promote DNA replication (e.g. E2F1, CCNE2, CDC45). A third, related project will extend our discovery that EGFR/ERK signaling promotes mitochondrial biogenesis and a metabolic shift that activates cell growth and proliferation, in both Drosophila and human cells. New paradigms explaining how growth is coupled to cell division can present novel strategies and gene targets for the diagnosis, treatment, and prevention of common diseases involving dysregulated cell proliferation. Two final projects focus on how the Drosophila intestine senses and responds to damage. This is relevant to proliferative control because, for most epithelia, damage initiates a regenerative response that comprises growth signaling, stem cell activation, and regulated cell division. Epithelial damage responses also stimulate inflammation, giving further clinical relevance. To understand this regenerative response, genomics approaches (ATAC-seq, Cut&Tag, RNA-seq) will be used to identify the target genes of damage-dependent Cytokine/Jak/Stat signaling. In addition, we are conducting a unique, high-throughput functional screen using enterocyte-targeted RNAi’s to identify all of the Drosophila genes required to sense gut epithelial damage and initiate regeneration. A comprehensive catalog of the genes used in tissue damage responses will be a foundational resource for extending our understanding of stress- activated-, inflammatory-, and regenerative signaling. This will in turn present new approaches for: 1) controlling inflammation during infections and in auto-immune diseases, and: 2) stimulating regeneration to combat degenerative disease, and to aid tissue engineering.