REGULATION OF CELL GROWTH AND PROLIFERATION - PROJECT SUMMARY This renewal application addresses the regulation of cell growth and proliferation, a topic that is fundamental to cell and developmental biology, and directly relevant to the many human diseases in which cell growth is dysregulated (e.g. degenerative diseases, inflammatory conditions, benign and malignant tumors). My group’s NIGMS-supported research, dating back to 1994, has maintained the singular goal of understanding how cell proliferation is regulated in vivo, in the complex environment of the animal body. We focus on basic issues: how cell signaling drives cell growth and the cell cycle, how cell metabolism is regulated and impacts cell cycle progression, how environmental, inter-cellular signaling and intra-cellular molecular interactions regulate these processes in tissues. We specialize in genetic approaches in Drosophila, with a current focus on the intestinal epithelium, but we also seize opportunities to translate our findings using human cells. One ongoing project is testing our hypothesis that growth-dependent translation of messenger RNAs that encode limiting cell cycle regulators determines whether, and how fast, cells proliferate. We validated this idea in Drosophila and human cells, and are currently investigating how upstream signaling interfaces with the growth-dependent translation of cell cycle factors. A second project focuses on how EGFR/RAS/ERK and Cytokine/JAK/STAT signaling activate intestinal stem cells (ISC) for proliferation during gut regeneration. We are investigating how ERK-dependent signaling interfaces with stem cell metabolism, and mapping the gene targets of JAK/STAT signaling that mediate ISC proliferation and differentiation. A third project focusses on how intestinal epithelia sense and respond to environmental damage, such as infections. This is important because, in most organs, damage triggers a signaling cascade that promotes stem cell activation, growth and division. We believe tissue damage sensing is essential for not only stress-dependent regeneration, but also tissue maintenance, homeostasis and longevity. To understand this process we are applying gene expression profiling and genetic screening to identify all the Drosophila genes required to sense gut epithelial damage and initiate regeneration. Characterizing these genes is essential to gain a full understanding of stress-activated, inflammatory, and regenerative signaling. A fourth and final project uses genetic screening and gene function analysis to learn how ISCs re-establish quiescence at the conclusion of a regenerative episode. This process has been studied very little, but it is critical for maintaining tissue homeostasis and preventing chronic inflammation and pre-cancerous growth. Overall, these projects will produce fundamental new insights explaining how cell growth and proliferation are regulated. In so doing, they will also present novel strategies and gene targets for the diagnosis, treatment, and prevention of the many common diseases that stem from dysregulated cell proliferation, including conditions of tissue atrophy, inflammation, and all types of cancer.
