Project 458792

Chemotherapy and radiotherapy, designed to kill cancer cells, can also damage normal cells of the body, resulting in short-term and long-term side-effects and toxicities. This is particularly problematic for young cancer patients, whose body is still developing. Hematopoietic stem cells (HSCs) are the precursors of all the cells of the blood, and their damage can therefore results in immunosuppression, anemia, and other side-effects. We propose that further understanding of HSC responses to genotoxic stress may in the long-term allow to better predict and minimize such side-effects of cancer therapies. Here we for the first time report the induction of P2X7 receptor protein on HSCs in response to genotoxic stress, and provide preliminary data indicating that P2X7 contributes to HSC dysfunction in this setting. In this project, we will characterize the regulation of P2X7 expression on HSCs and its role in HSC dysfunction in the context of genotoxic stress. Importantly, P2X7 is widely investigated as a drug-target for other disorders, with several pharmacological agents targeting P2X7 already available and safely administered to human in other studies. The long-term vision for our research project is that modulation of P2X7 activities with such drugs may partly protect HSCs and HSC-derived blood cells of cancer patients from off-target side-effects and toxicities of cancer therapies.