Polyphosphate Utilization in Living Systems of Mammals and their Effects

Objective

PULSE: Polyphosphate Utilization in Living Systems of Mammals and their Effects. Here, we propose to uncover how mammalian systems utilize polyphosphate (polyP) and what roles it may play in health. First, we introduce a novel approach to understand how polyP levels affect cellular activity. We propose measuring metabolic activity, transcriptional differences, and morphological conditions induced by manipulating the abundance of polyP in specific subcellular compartments. To do this, we have developed a system to express either polyphosphate kinase (PPK) or exopolyphosphatases (PPX) in specific compartments to increase or decrease the polyP levels, respectively. We further propose to interrogate the role polyP plays in liver health and acute liver damage caused by acetaminophen (APAP) toxicity. We will use a novel mouse model with ectopic expression of PPX to decrease the level of polyP present in the liver to determine the effect of polyP abundance on liver tissue response to acute APAP injury. We will analyze the pathology of the tissue through multiple methods including serum biomarkers, histopathology, immunohistochemistry, intravital multi-photon imaging, and pulsed-infrared laser-based tissue proteomics. In addition, using human patient samples from the UKE facility, we can analyze polyP levels in human tissue based on human-specific pathologies, allowing us to expand our study to include patient-relevant data. At the conclusion of this project, we will substantially expand the baseline understanding of how mammalian systems utilize polyP. With the work from our mouse model, we will have a clearer understanding of what role polyP plays in the health of mammals. The additional data we will generate from human patient samples will allow us direct understanding into the role of polyP in human health as well.