Pharmacological CBP/p300 histone acetyltransferase inhibition to therapeutically modulate leukocyte biology and promote host defenses

• Applicant: Nikolai Pirmin Jaschke, Ph.D.
• Subject Area: Hematology, Oncology ; Endocrinology, Diabetology, Metabolism
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 525808956

The bone marrow is the central reservoir for leukocytes, which can be recruited into the blood stream and distant tissues on demand (e.g. in response to infection) within minutes to hours. Leukocyte compartment sizes in the blood and other tissues fluctuate physiologically in humans and can be severely deviated from the physiological set-point in the context of diseases such as bone marrow failure and acute leukemia. Although mechanisms controlling leukocyte compartment sizes have been extensively studied, pharmacological approaches to modulate bone marrow niche maintenance, leukocyte mobilization and trafficking remain limited. Identifying molecular checkpoints of these processes could aid in improving therapeutic outcomes in a wide range of diseases, including opportunistic infections in immunocompromised hosts (e.g. toxic bone marrow injury following chemotherapy). This project seeks to explore the therapeutic utility of pharmacological CBP/p300 histone acetyltransferase (HAT) inhibition to modulate leukocyte biology and boost host defenses in the context of intact and defective hematopoiesis. In my preliminary studies, I could show that CBP/p300 HAT inhibition triggers a transient leukocytosis, which likely derives from bone marrow mobilization. I speculate that local (Cxcl12 signaling, integral expression) and neurohumeral (sympathetic nervous system, glucocorticoids) changes impinge on the bone marrow to favor leukocyte egress. I want to study this hypothesis over the next 2 years and define a potential clinical application of these observations in a mouse model of polymicrobial sepsis in the context of bone marrow injury.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Andrew Wang, Ph.D.