Uncovering Non-canonical Roles of Phosphagen Systems in Stress Resilience Using C. elegans

About This Grant

Abstract This proposal seeks to understand emerging non-canonical roles of phosphagen kinases in cellular and organismal stress responses. Phosphagen kinases are a class of enzymes that include creatine kinases. They are well-known to support energy balance, but other functions are less well-understood. Recent research suggests that augmenting the activity of these enzymes may be sufficient to increase cellular stress responses, which are important in preserving tissue health during aging and disease. This makes phosphagen kinases potentially exciting targets for aging and disease intervention, but we still don’t fully understand how they work. Furthermore, their functions may depend on which tissues different versions of the enzymes are present in and what they are doing in each tissue. Understanding tissue-specific roles of enzymes is challenging in humans and laboratory models such as rodents and cell culture. In contrast, the roundworm, C. elegans, is a well-established and efficient model system that is perfectly suited for addressing these questions, and it shares many genes and biological processes in common with humans. In this study, we propose to use this model to: 1) Identify which of three different versions of phosphagen kinases support tolerance to diverse stresses 2) Test the hypothesis that phosphagen kinases protect cells by acting similarly to antioxidants and preserving the function of energy machinery. Simultaneously, identify which tissues are most affected by phosphagen kinase function and sensitive to its loss through tissue-specific genetic manipulations. 3) Determine whether phosphagen kinase function changes the way other enzymes and genes act to support stress response using new genetic sequencing technologies. Altogether, this work will illuminate mechanisms of phosphagen kinase function under stress. paving the way for novel aging and disease interventions. Furthermore, through this funding, at least 9 undergraduate students and 2 graduate students will be trained in state-of-the-art biomedical science, fostering the next generation of scientists and America’s continued superiority in biomedical research.