Project Details
Projekt
The regenerative potential of neutrophils in neonatal hypoxic-ischemic brain injury
Subject Area
Pediatric and Adolescent Medicine
Term
since 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 494550180
Perinatal asphyxia resulting in hypoxic-ischemic encephalopathy (HIE), occurring in 1 – 6 live births, is the worldwide leading cause of death and disability in children. The only recommended therapy hypothermia is limited in severe cases and needs to be initiated within the first 6 hours of life. New and/or additional treatment strategies are urgently needed with the pre-requisite of an increased understanding of the complex HIE-pathophysiology, involving not only cells of the central nervous but also of the immune system. A major hallmark of HIE-induced inflammatory responses is infiltration of peripheral immune cells, with neutrophils representing the majority. Although we have previously proven the detrimental role of these cells in the early phase of neonatal brain injury caused by hypoxia-ischemia (HI), their impact on endogenous delayed HI-induced regenerative processes is unknown. This is of major importance, considering the increasingly recognized neutrophil plasticity, suggesting the existence of repair neutrophils releasing a plethora of mediators such as growth and proangiogenic factors. We hypothesize that neutrophils in the late disease phase contribute to secondary neuroprotection and endogenous regeneration, involving angiogenesis and vascular remodeling. A well-described concept of neutrophil heterogeneity is derived from cancer pathology, revealing anti-inflammatory and pro-angiogenic functions of neutrophils in the absence of type I interferon (IFN) signaling. However, the existence of reparative neutrophils and the potential involvement of type I IFNs in their function following neonatal HI is unknown.Using state of the art proteomics and a variety of functional assays including organoid cultures, we will perform in depth characterization of neutrophils, derived from injured brains and different organs to determine neutrophil heterogeneity in the time course after HI. Place and mode of action will be investigated by antibody-mediated peripheral neutrophil depletion and inhibition of neutrophil infiltration into injured brains acutely and in a delayed fashion after the insult. In depth behavioral phenotyping will be combined with immunohistochemistry, proteome profiling and novel 3D imaging techniques to assess the impact of neutrophils on neurodevelopment, regenerative processes, angiogenesis and vascular remodeling. To determine the influence of type I interferon signaling on neutrophil function, we will use novel transgenic mouse lines, enabling cell-specific neutrophil visualization and manipulation. In a translational approach, these in vivo models will be combined with therapeutic hypothermia to evaluate potential synergistic effects. By the combination of innovative techniques and complex in vivo experiments this project will provide new mechanistic insights into HIE pathophysiology and identify potential novel therapeutic targets. Modulation of these will have high potential to be implemented in standard clinical care.
DFG Programme
Research Grants
