CAREER: Discovering the interplay between polyploidy and innate immunity

About This Grant

This integrated research and educational project will yield fundamental knowledge on how wound healing is regulated by cell growth and its contribution to an animal’s defense against infection. The project will train and instruct graduate and undergraduate students in both the laboratory and classroom. Students will gain hands-on research experience, applying an interdisciplinary approach utilizing principles of cell biology, genetics, and microbiology. Undergraduate students (up to 120 per year) enrolled in an annual Introduction to Genetic course at Boston College will learn and apply quantitative analysis skills in how to conduct, score, and identify mutants from a genetic screen, revealing previously unknown regulators of cell growth and wound healing. The identification of genes that regulate wound healing will provide a pipeline to discover novel therapeutic targets to improve human health and prevent disease. The scientific and educational discoveries from this project will be published and shared with the general public as a model for how to enhance scientific communication, discovery, and rigor in the next-generation of STEM researchers in the biological sciences. Wound healing requires either cell division or cell growth. Cells can grow orders of magnitude by becoming polyploid, which is due to the more than doubling of a cell’s diploid genome. Polyploid cells often arise under conditions of stress to adapt to abiotic and biotic stressors, including tissue injury. During wound healing, polyploidy has been found to be advantageous as it allows healing in the presence of genotoxic stress and restores tissue mechanics in animal models. Injury is also known to introduce bacteria and other microorganisms. However, it remains unknown how the innate immune response interplays with polyploid cell growth to defend against infection. Using the fruit fly as a model, production of antimicrobial peptides was found to be upregulated in the wound-induced polyploid cells. In addition, a serine protease in the conserved (Toll) innate immune signaling pathway was found to be required for polyploid cell growth. Therefore, the following aims will be addressed: (1) to determine how polyploidy activates the innate immune response, (2) to determine how serine proteases in the innate immune pathway regulate polyploidy, and (3) to identify other transcription factors that initiate and control the extent of polyploidy post injury. These aims will integrate with the instruction and mentorship of students at Boston College, providing training in how interdisciplinary approaches can spur scientific discoveries. In doing so, this study will be the first to elucidate how polyploidy and innate immunity are intertwined to regulate wound closure, inflammation, and the biotic stress of microbial infection. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.