The role of hematogenous monocyte/macrophage responses for vascular pathology and regeneration in CNS injury

• Applicant: Professor Dr. Sebastian Jander
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: from 2015 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 277319053

Vascular damage is an important, but incompletely understood component of spinal cord injury (SCI) that needs to be quickly repaired in order to avoid devastating secondary injury due to progressive hemorrhage and edema. SCI induces a massive inflammatory response with activation of resident CNS macrophages/microglia as well as infiltration of monocytes, granulocytes, and lymphocytes from the blood stream. Our recent findings in ischemic stroke indicate that hematogenous recruitment of inflammatory monocytes and their subsequent differentiation into repair-promoting macrophages is essential for the stabilization of neovessels and the prevention of hemorrhage in the infarct border zone. However, inflammatory processes may also cause exacerbation of injury and build up impediments to axonal regeneration after CNS injury. Given this fundamental dilemma, we aim to develop therapeutic strategies that selectively suppress debilitating consequences of inflammation whilst maintaining or enhancing its functions for neurovascular regeneration. We postulate that early recruitment of hematogenous monocytes is indispensable for vascular repair whereas delayed monocyte/macrophage responses cause adverse remodeling with fibrotic scar formation that in turn interferes with axon regeneration. To this end, we will study hematogenous monocyte/macrophage responses in mouse models of SCI and its functional role for vascular pathology and regeneration in SCI. We will address the following key questions: 1.) What is the time course and mechanism of hematogenous monocyte/macrophage recruitment in SCI? 2.) Are there differences between traumatic and ischemic SCI, and between different CNS compartments (spinal cord vs. optic nerve vs. brain injury)? 3.) What is the functional role of early vs. delayed MO/MP responses for reestablishment of vascular barrier functions, fibrous scarring, and axonal regeneration? 4.) What are the molecular targets for novel therapies?

• DFG Programme: Research Grants
• Co-Investigator: Privatdozent Dr. Michael Gliem