Periodic Reporting for period 1 - OxyBaby (The Inflammasome: a novel therapeutic target for the treatment of Hypoxic Brain Injury in Neonates)
Période du rapport: 2020-09-01 au 2022-08-31
Excitingly, recent studies have shown that inhibiting the inflammasome complex and inflammatory pathways is a favourable target for the treatment of adult neurological disorders including stroke, Parkinson’s and Alzheimer’s. The overall objectives of this project are to explore the role of the inflammasome complex and microRNA-155 in the young hypoxic injured brain and to test targeting these pathways for treatment of the injuries. We hope to identify the exact timing and activation of these pathways following hypoxic injury and to then target components of the pathways to attempt to block the development of cerebral palsy/epilepsy using our preclinical models.
Conclusion of the action: Transgenic mouse models are critical for molecular interrogation of microRNA function in the injured brain. The work in Oxybaby has resulted in the development of novel transgenic mouse model that allows us to analyse the role of the inflammatory microRNA-155 in a discrete immune cell population of the brain called microglia. This was invaluable in understanding the role of inflammation after hypoxic brain injury in the newborn brain. Deletion of microRNA-155 in the microglia of our transgenic mouse model reduced inflammation and improved motor function after hypoxic injury. Additionally, these transgenic mice had a reduction in the number and severity of seizures. This work will be continued in preclinical projects testing microRNA-155 inhibitors that are delivered shortly after injury for the treatment of hypoxic brain damage and neuroinflammation that can lead to epilepsy.
Oxybaby results also demonstrated that inflammasome inhibitors can have a significant effect on inflammation in the brain up to at least three days after injury in our preclinical model. This is a critical time point when perpetual inflammation is highly detrimental to newborn brain health and function. Ongoing work is confirming the beneficial effects of inflammasome inhibition on negative outcomes of hypoxic injury including poor motor function during development.
During the course of the project different opportunities arose and we developed a novel transgenic mouse model that allowed us to analyse the role of the inflammatory microRNA-155 in a discrete immune cell population of the brain called microglia. Deletion of microRNA-155 in these transgenic mice suppressed inflammation, reduced seizure severity and improve motor function outcomes in the preclinical model of hypoxia induced seizures. This transgenic mouse model will guide future studies which attempt to block or prevent epilepsy development.
The work completed as a Marie Sklodowska Curie fellow has to date resulted in 1 preprint article, 2 conference talks, 2 invited institutional talks, 1 additional journal article and 1 review currently in preparation. The Marie Sklodowska Curie fellow has also secured an academic position in an Irish University, establishing their own research group and currently supervises 1 PhD and 1 Postdoctoral researcher.
A particularly worrying aspect of hypoxic brain injury in newborns is increased risk among males and many of the current treatments are more effective in females. We are excited that the OxyBaby project found that targeting miR-155 in immune cells in the brain reduced seizure scores and improved motor function outcomes in both males and females. We will continue this work and will focus on designing a targeted microRNA-155 therapy that can be delivered shortly after hypoxic injury to patients as a strategy to help improve both short term and long-term outcomes. This has the potential to improve the quality of life patients with hypoxic brain injuries worldwide.