Mechanisms that regulate cellular responses to phosphate - PROJECT SUMMARY/ ABSTRACT This research seeks to understand how mammalian cells respond to fluctuating extracellular phosphate levels. Inorganic phosphate (Pi) is a critical component of life – an essential regulator of numerous cellular functions, including energy metabolism, cellular signaling, membrane integrity, and nucleic acid synthesis. To ensure these critical activities are functioning effectively, cells must sense, acquire, and maintain intracellular Pi at suitable levels. Indeed, disruption of Pi homeostasis has major consequences for cellular function and organismal health. For mammals, the focus of this proposal, too little systemic Pi can cause undermineralized bone, as in rickets, as well as muscle weakness, while complications from even modest Pi increases include inflammation, anemia, extraskeletal calcifications, and soft tissue damage. While the hormones that regulate the endocrine control of circulating Pi levels are beginning to be understood, we lack a detailed, mechanistic understanding of the cellular handling of Pi. Our preliminary work in understanding how osteogenic cells function in the endocrine control of serum Pi homeostasis identified Pi response components that appear conserved across cell types. In our work we identified Pi-responsive signaling proteins such as RGS14 (regulator of G protein signaling isoform 14) and SGK1 (serum/glucocorticoid regulated kinase 1), as well as changes in cellular Pi uptake and efflux in response to both long-term and short-term fluctuations in extracellular Pi, suggesting the presence of both a long-term Pi adaptation mechanism and a short-term Pi sensing and response. In this proposed research, we are motivated by these findings to understand the control of cellular phosphate homeostasis more generally across mammalian cells. We seek to understand how distinct mammalian cell types may differentially sense, respond to, and process Pi to ensure cellular and organismal homeostasis. Over the five-year funding period, the goals of this project are to initially: (i) determine how mammalian cells control Pi uptake and efflux in response to changes in extracellular Pi, (ii) dissect the signaling pathways that regulate the cellular response to these fluctuations in extracellular Pi, and then using these findings (iii) determine how perturbations in Pi regulatory mechanisms in different tissues disrupt organismal function. As control of cellular Pi homeostasis is key to overall organismal health, the successful completion of this work will establish the molecular mechanisms responsible for controlling cellular phosphate homeostasis, with important implications for the treatment of phosphate-related diseases.
