The role of the innate immune receptor MDA5 and inflammatory signaling in hematopoietic regeneration after chemotherapy.

• Applicant: Dr. Nina Cabezas-Wallscheid, since 12/2021
• Subject Area: Hematology, Oncology ; Developmental Biology
• Term: from 2021 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 465439136

Our blood is responsible for many functions, including oxygen transport and immunity, that is the organism’s ability to fight off infections. All blood cells are produced by hematopoietic stem cells (HSCs), which are born while we are embryos and reside in our bone marrow throughout our adult life. There, HSCs are protected from external dangers by remaining hidden and in a quiescent state, thus dividing rarely. However, when the organism faces a challenge like an infection or heavy blood loss or even during chemotherapy, when many of the our blood cells are killed, HSCs exit quiescence and start to divide to replenish the blood cells lost during these challenges. The more times HSCs are forced to exit quiescence throughout our life, the less efficient they become at facing a next challenge, with the potential danger of ultimate exhaustion. Even further, patients undergoing chemotherapeutic treatments depend heavily on HSC activation to replenish their hematopoietic system. It is therefore very important to understand the mechanisms that HSCs use to exit quiescence and proliferate. The goal of this proposal is to understand the molecular mechanisms that govern HSC activation after chemotherapy. Our preliminary results point to the fact that the innate immune receptor MDA5 that is mostly known for its role in recognizing pathogens, is actively participating in HSC activation. HSCs of mice lacking MDA5 resist to activation and, consequently, keep their fitness and are more efficient at producing blood cells long-term. In this proposal, we would like to understand the role of MDA5 in HSC activation and how its presence or absence is reflected in gene expression and the cell metabolic and epigenetic status, cellular features controlling the switch between activation and quiescence. Completion of this proposal will lead to a better understanding of the mechanisms behind HSC activation and the role of innate immune receptors in this function. Our research will be beneficial for patients undergoing chemotherapeutic treatments.

• DFG Programme: Research Grants
• Ehemalige Antragstellerin: Eirini Trompouki, Ph.D., until 11/2021