Modulating the macrophage epigenome by using HDAC3 inhibitors, to promote recovery after spinal cord injury. (R-7297)

Spinal cord injury(SCI) is a devastating disorder affecting over two million people worldwide. Patients suffer from severe losses of motor, sensory and autonomic nervous system functions. Currently, the standard care of SCI patients is limited to rehabilitation and immunosuppressive treatment. Specific immunomodulation is a key goal to replace this non-specific immunosuppression which is the state of the art until today. Pro-inflammatory M1 Macrophages are central players in the inflammatory response after SCI. They exert detrimental effects by secreting multiple pro-inflammatory and neurotoxic factors and attack dystrophic axons as a major cause of functional impairment. A great but yet underexplored potential source for immunomodulation after SCI are histone deacetylation inhibitors (HDACi). In this project we focus on blocking HDAC3 in macrophages, which is well-known to control macrophage polarization towards the detrimental M1 phenotype. Thus, we aim to inhibit the endogenous M1 macrophages via HDAC3 in order to reduce axonal damage and functional impairment in a well-established SCI mouse model. To address these questions in vitro and in vivo we will use broad-spectrum HDACi and specific HDAC3 inhibitors administered systemically as well as via liposomes which specifically target M1 macrophages as well as mice with a specific HDAC3-deficiency in macrophages. Evaluating the use of HDACi for inducing repair after SCI may lead to new therapeutic approaches in neurotrauma.

Keywords:SPINAL CORD INJURY

Disciplines:Morphological sciences