Regulatory mechanisms of temporal microglia phenotype expression in a neonatal rat model of infection-sensitized hypoxic ischemic brain injury

• Applicant: Professor Dr. Hemmen Sabir
• Subject Area: Pediatric and Adolescent Medicine
• Term: from 2019 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 422493683

Perinatal asphyxia, describing the lack of oxygen and blood flow before, during, or just after birth, is one of the leading causes of global child death. It can affect all organ systems, however the most frightened resulting condition, predominantly affecting the newborn brain, is hypoxic ischemic encephalopathy (HIE) often resulting in mortality or significant morbidity in later life. Even though therapeutic hypothermia (TH) has become standard treatment for HIE, around 50% of cooled newborns still die or develop severe disability. Early identification of these non-responders is not possible yet, but urgently needed, as they might benefit from additional treatment options. Perinatal infection increases the vulnerability to hypoxic-ischemic injuries and negatively influences the prognosis of affected newborns. We have developed an animal model of infection-sensitized hypoxic-ischemic brain injury (double-hit model) and showed that TH is not a viable treatment option in this model, characterizing one group of non-responders. This double-hit model gives us the opportunity to investigate the underlying mechanisms in a defined group of non-responders. We have shown that microglia cells are key players in our double-hit model and contribute to brain injury. As the interaction and regulation of the double-hit is not known yet, this project aims to describe the regulatory mechanisms responsible for microglia activation and different microglia phenotype expression in our double-hit model of inflammation-sensitized hypoxic-ischemic brain injury in newborn rats. We will focus on the role of micro-RNAs in microglia modulation and phenotype expression over time. Additionally, we will investigate the role of the NLRP3 inflammasome, its impact during microglia activation, its regulation by miRNAs and its impact on severity of brain injury in our double-hit model. Last, we will investigate the potency of an additional neuroprotective treatment (Erythropoietin) in our double-hit model, describing its influence and pathway on microglia phenotype activation. The aim is to develop robust biomarkers and therapeutic targets, which will be tested in clinical studies, early identifying non-responders to therapeutic hypothermia.

• DFG Programme: Research Grants
• Co-Investigators: Professor Dr. Ivo Bendix; Dr. Josephine Herz